ABT-450 combined with ritonavir, in addition to ABT-333 and ribavirin: A race for an interferon-free regimen to cure HCV infection

Journal of Hepatology
Volume 59, Issue 4 , Pages 885-888, October 2013

Tarik Asselah

Received 11 March 2013; received in revised form 15 May 2013; accepted 15 May 2013. published online 28 May 2013.

Abbreviations: DAA, direct-acting antivirals, PegIFN, pegylated interferon, SVR, sustained virological response, eRVR, extended rapid virological response, RVR, rapid virologic response

Keywords: Direct-acting antivirals, Sustained virological response, Chronic hepatitis C, NS5A inhibitors, Safety, Resistance

COMMENTARY ON:

Exploratory study of oral combination antiviral therapy for hepatitis C. Poordad F, Lawitz E, Kowdley KV, Cohen DE, Podsadecki T, Siggelkow S, Heckaman M, Larsen L, Menon R, Koev G, Tripathi R, Pilot-Matias T, Bernstein B. N Engl J Med. 2013 Jan 3;368(1):45-53. Copyright © 2012 Massachusetts Medical Society. Abstract reprinted with permission from Massachusetts Medical Society. http://www.ncbi.nlm.nih.gov/pubmed/23281975

Abstract. Background: There is a need for interferon-free treatment regimens for hepatitis C virus (HCV) infection. The goal of this study was to evaluate ABT-450, a potent HCV NS3 protease inhibitor, combined with low-dose ritonavir (ABT-450/r), in addition to ABT-333, a nonnucleoside NS5B polymerase inhibitor, and ribavirin, for the treatment of HCV infection.

Methods: We conducted a 12-week, phase 2a, open-label study involving patients who had HCV genotype 1 infection without cirrhosis. All patients received ABT-333 (400mg twice daily) and ribavirin (1000 to 1200mg per day) and one of two daily doses of ABT-450/r. Groups 1 and 2 included previously untreated patients; group 1 received 250mg of ABT-450 and 100mg of ritonavir, and group 2 received 150mg and 100mg, respectively. Group 3, which included patients who had had a null or partial response to previous therapy with peginterferon and ribavirin, received daily doses of 150mg of ABT-450 and 100mg of ritonavir. The primary end point was an undetectable level of HCV RNA from week 4 through week 12 (extended rapid virologic response).

Results: A total of 17 of the 19 patients in group 1 (89%) and 11 of the 14 in group 2 (79%) had an extended rapid virologic response; a sustained virologic response 12 weeks after the end of treatment was achieved in 95% and 93% of the patients, respectively. In group 3, 10 of 17 patients (59%) had an extended rapid virologic response, and 8 (47%) had a sustained virologic response 12 weeks after therapy; 6 patients had virologic breakthrough, and 3 had a relapse. Adverse events included abnormalities in liver-function tests, fatigue, nausea, headache, dizziness, insomnia, pruritus, rash, and vomiting.

Conclusions: This preliminary study suggests that 12 weeks of therapy with a combination of a protease inhibitor, a non-nucleoside polymerase inhibitor, and ribavirin may be effective for treatment of HCV genotype 1 infection. (Funded by Abbott; ClinicalTrials.gov number, NCT01306617.)

Introduction

Two direct-acting antivirals (DAAs), telaprevir and boceprevir, are given in combination with pegylated interferon (PegIFN) and ribavirin to genotype 1 HCV infected patients. PegIFN has several side effects and many patients are not eligible or have failed this treatment. Therefore, there is a need to develop an IFN-free regimen. Ideally, the future IFN-free regimen should have a high efficacy, favorable safety profile, and high barrier to resistance [1]. This article is discussing the impressive data from the IFN-free trial with ABT-450 based regimen [2], [3].

ABT-450 is an inhibitor of NS3/4A protease that is metabolized by cytochrome P450 isoform 3A (CYP3A). ABT-450 is co-administered with ritonavir (ABT-450/r), a CYP3A inhibitor, to enhance ABT-450 exposure. ABT-450/r is dosed once daily. ABT-267 is an NS5A inhibitor that is dosed once daily. ABT-333 is an NS5B polymerase non-nucleoside inhibitor dosed twice daily.

ABT-450 boosted with ritonavir (ABTr), in addition to ABT-333, and ribavirin for HCV genotype 1 infected patients (pilot and co-pilot studies)

Study design 

Impressive results were reported recently from a phase 2a multicenter open-label study [2]. Groups 1 (n=19) and 2 (n=14) included naïve patients, and group 3 (n=17) included null (n=7) or partial responders (n=10) to previous therapy (Fig. 1A). All patients received triple therapy with ABT-450r, ABT-333, and ribavirin, for 12 weeks.

Fig. 1. Trial designs and results of studies with ABT-333 based regimen. (A) Phase 2a, multicenter, open-label, trial design [2]. All patients received ABT-333 (400mg twice daily) and ribavirin (1000–1200mg per day) and one of two daily doses of ABT-450/r. Groups 1 and 2 included previously untreated patients; group 1 received 250mg of ABT-450 and 100mg of ritonavir, and group 2 received 150mg and 100mg, respectively. Group 3, which included patients who had had a null (n=7) or partial response (n=10) to previous therapy with PegIFN/ribavirin, received daily doses of 150mg of ABT-450 and 100mg of ritonavir. ABT-450, NS3 protease inhibitor, boosted with ritonavir (ABT-450/r); ABT-333, non-nucleoside NS5B polymerase inhibitor. (B) Phase 2a, multicenter, open-label, trial results [2]. A total of 17 of the 19 patients in group 1 (89%) and 11 of the 14 in group 2 (79%) had an extended rapid virologic response; an SVR 12weeks after the end of treatment was achieved in 95% and 93% of the patients, respectively. In group 3, 10 of 17 patients (59%) had an extended rapid virologic response, and 8 (47%) had an SVR 12weeks after therapy; 6 patients had virologic breakthrough, and 3 had a relapse. HCV RNA<LDQ_{TD or TND} (<25IU/ml); eRVR=extended rapid virological response defined as undetectable HCV RNA from week 4 through week 12.

End points 

The primary end point was the percentage of patients with undetectable HCV-RNA from week 4 through week 12 (extended rapid virologic response, eRVR). Secondary end points included patients with HCV-RNA below 25IU/ml at week 4 (rapid virologic response, RVR), at week 12, and 12weeks after the end of treatment (sustained virologic response (SVR)). SVR12 has been demonstrated to be as relevant as SVR24 under PegIFN/ribavirin [4]. COBAS TaqMan HCV Test, version 2.0 was used, with a lower limit of quantitation of 25IU/ml and a lower limit of detection of 15IU/ml.

Efficacy in naïve patients 

17/19 patients in group 1 and 11/14 in group 2 had an eRVR (Fig. 1B). None of the patients in group 1 or 2 had virologic breakthrough and none who completed treatment had a relapse; all patients who completed treatment had an SVR12. All 18 patients who completed treatment in group 1 had undetectable HCV RNA 48weeks after treatment. 2/13 patients who completed treatment in group 2 discontinued the study after week 12 of follow-up; the other 11 patients had undetectable HCV 48weeks after treatment.

Efficacy in patients with null or partial response to previous therapy 

6 patients had virologic breakthrough during treatment, including 1 who mistakenly took only 50mg of ABT-450 daily for the first 3weeks and who never had an HCV RNA lower than 25IU/ml. Ten patients had an eRVR. Three patients had a relapse 2weeks after treatment, and 8 had an SVR12. 3/7 patients with a null response and 5/10 with a partial response had SVR12. In most cases, virologic failure was associated with the emergence of variants with substitutions in both NS3 and NS5B, at positions known to confer resistance in vitro to ABT-450 and ABT-333, respectively.

Safety

No deaths or serious adverse events occurred. One patient in group 1 discontinued drugs owing to aminotransferases increase at week 2. The elevated aminotransferase levels were not associated with an increased bilirubin level and improved after treatment. The most frequent events were fatigue, nausea, headache, dizziness, insomnia, pruritus, rash, and vomiting. Most events were mild. Four adverse events were classified as severe: fatigue, pain, vomiting, and hyperbilirubinemia. None of these events led to drug discontinuation.

ABT-450/r, ABT-267, ABT-333 and ribavirin (Aviator study) 

The Aviator phase 2b study assesses the safety and efficacy of ABT-450/r, ABT-267 (NS5A inhibitor), ABT-333, and ribavirin in non-cirrhotic naïve patients and prior PegIFN/ribavirin null-responders for 8, 12 or 24weeks (Fig. 2A) [3]. Results are summarized in Fig. 2B. For the 12-week triple-DAA regimen with ribavirin being studied in phase 3 trials: 96% of treatment-naive patients achieved SVR; and 93% of prior null responders achieved SVR. Comparable high response rates were obtained in the 12- or 24-week arms, supporting a 12-week treatment duration. Treatment was well tolerated. Four of 448 patients in the 8- and 12-week arms discontinued treatment because of adverse events. The most common adverse events were fatigue and headache.

Fig. 2. Aviator study. (A) Trial design [3]. This phase 2b study assesses the safety and efficacy of ABT-450/r (dosed 100/100mg to 200/100mg QD), ABT-267 (25mg QD), ABT-333 (400mg BID), and ribavirin in non-cirrhotic treatment-naïve patients and prior PegIFN/ribavirin null responders for 8, 12 or 24weeks. ABT-450, NS3 protease inhibitor, boosted with ritonavir (ABT-450/r); ABT-267, NS5A inhibitor; ABT-333, non-nucleoside NS5B polymerase inhibitor. (B) Results from the Aviator study [3]. SVR in treatment-naїve genotype 1 (GT1) patients and in GT1 null responder patients.

Discussion: what have we learned? 

First, for naive genotype 1 patients without cirrhosis («easy-to-cure patients»), this preliminary study suggests that the all-oral combination of 2 DAAs (ABT-450/r, ABT-333), and ribavirin for 12weeks is associated with a high SVR rate. According to subtype, no virologic failures occurred among the 26 genotype 1a naïve patients.

Second, this regimen (ABT-450/r, ABT-333, and ribavirin) is less effective in null or partial responders to previous therapy («difficult-to-cure patients»). Extending the treatment duration beyond 12weeks may not be an option since most of the virologic failures occurred during treatment. We do not really understand why treatments including DAAs are less effective in treatment-experienced patients when compared to naïve patients, even in the absence of IFN therapy. Innate immunity may still have a role in HCV clearance with these DAAs [5]. For previous non-responders, more potent combination with different compounds may be needed. The combination of several DAAs (ABT-450/r, ABT-267, ABT-333, and ribavirin) in non-cirrhotic prior null-responders provides excellent preliminary results. Moreover, PegIFN may remain an option in previous non-responders (or as a rescue therapy), since a high SVR rate was achieved when two DAAs were combined with PegIFN/ribavirin [6].

Third, we will have to wait for more data, with a larger number of patients, including difficult-to-cure patients with cirrhosis and previous non-response. Of course, phase 3 studies will provide more information about safety, effectiveness, and drug-drug interactions, especially when several new drugs are developed in the same regimen (and ABT-450 is boosted with ritonavir).

Conclusions

Finally, ABT-450-based regimen showed impressive results. It is unclear whether ribavirin will remain an important agent. For easy-to-cure patients, “genotype 1b with mild disease”, ribavirin may be not useful. For difficult-to-cure patients, “cirrhosis with prior non-response”, an intensive regimen may be necessary.

The phase 3 program is ongoing. The DAAs in the studies include ABT-450/r (protease inhibitor and ritonavir), ABT-267 (NS5A inhibitor) and ABT-333 (non-nucleoside polymerase inhibitor). Treatment duration will be 12weeks in non-cirrhotic patients and 12 or 24weeks in cirrhotic patients. All patients will be followed for 48weeks post-treatment. Co-formulated tablets of ABT-450/r and ABT-267 will be used in phase 3 trials. (http://www.clinicaltrials.gov.)

There is a realistic hope for an oral regimen against HCV since several DAA combinations have reported interesting preliminary results (increased SVR, low resistance and a preliminary good safety profile) [7], [8], [9]. We have to take into account this important revolution, but remain cautious and await larger phase 3 data, especially regarding safety and drug-drug interactions. Finally, we wish a nice flight to Aviator, and we hope that in the near future an IFN-free regimen will be available for patients with HCV infection.

Conflict of interest 

Tarik Asselah is a speaker and investigator for BMS, Boehringer-Ingelheim, Tibotec, Janssen, Gilead, Roche, and Merck.

References 

Source

Slow regression of liver fibrosis presumed by repeated biomarkers after virological cure in patients with chronic hepatitis C

Journal of Hepatology
Volume 59, Issue 4 , Pages 675-683, October 2013

Thierry Poynard, Joseph Moussalli, Mona Munteanu, Dominique Thabut, Pascal Lebray, Marika Rudler, Yen Ngo, Vincent Thibault, Helmi Mkada, Frederic Charlotte, Françoise Imbert Bismut, Olivier Deckmyn, Yves Benhamou, Marc Antoine Valantin, Vlad Ratziu, Christine Katlama, FibroFrance-GHPS group

Received 31 March 2013; received in revised form 29 April 2013; accepted 8 May 2013. published online 28 May 2013.

Abstract

Background & Aims

Chronic hepatitis C is both a virologic and fibrotic disease and complications can occur in patients with sustained virologic response (SVR) with residual fibrosis. Due to the limitations of repeated biopsies, no studies have assessed the dynamic of fibrosis before and after treatment. Using biopsy as reference, FibroTest™ has been validated as a biomarker of fibrosis progression and regression, with similar prognostic values. The aim was to estimate the impact of SVR on the dynamic of fibrosis presumed by FibroTest™.

Methods

In a prospective cohort, the main end point was the 10-year regression rate of fibrosis, defined as a minimum 0.20 decrease in FibroTest™, equivalent to one METAVIR stage.

Results

A total of 933 patients with both repeated FibroTest™ and transient elastography were included. At 10years, among the 415 patients with baseline advanced fibrosis, 49% (95% CI 33–64%) of the 108 SVR had a regression, which was greater than in the 219 non-responders [23% (14–33%; p<0.001 vs. SVR)] and not lower than in the 88 non-treated [45% (10–80%; p=0.39 vs. SVR)] patients. In all 171 SVR, cirrhosis regressed in 24/43 patients, but 15 new cirrhosis cases occurred out of 128 patients, that is only a net reduction of 5.3% [(24–15)=9/171); (2.4–9.8%)]. Four cases of primary liver cancer occurred in SVR [4.6% (0–9.8)], and 13 in non-responders [5.6% (1.5–9.8); p=0.07].

Conclusions

In patients with chronic hepatitis C, and as presumed by FibroTest™, virological cure was associated with slow regression of fibrosis 10years later, a disappointing 5% decrease in cirrhosis cases, and a remaining 5% risk of primary liver cancer.

Keywords: Cirrhosis, FibroTest™, FibroSure, Elastography

PII: S0168-8278(13)00345-0

doi:10.1016/j.jhep.2013.05.015

© 2013 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.

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SVR Tied to Lower Progression, Mortality in HIV/HCV+ With Moderate Fibrosis - the importance of treating coinfected patients

Provided by NATAP

53rd ICAAC Interscience Conference on
Antimicrobial Agents and Chemotherapy
September 10-13, 2013, Denver CO

53rd ICAAC, September 10-13, 2013, Denver

from Jules: SVR reduced risk for AIDS progression and serious liver-related events in non-advanced as well as in patients with advanced HCV disease, thus as the authors say all HIV+ patients should be treated for HCV quick without undue delay, delaying therapy risks progression of HIV & HCV, even for patients with non-advanced disease but of course mores for patients with advanced disease. With the expected availability of new HCV therapies later this year but with peg interferon, and in 2014 IFN-free regimens with 95-100% SVR rates in phase 2 are expected to become available, coinfected patients should be treated without undue delay. If you view the slides below on "Rates of Events" you will see progression to AIDS, liver decompensation, HCC, overall mortality & liver-related mortality is reduced by as much as 10-fold.

Mark Mascolini

Sustained virologic response (SVR) to interferon plus ribavirin (IFN/RBV) with nonadvanced or moderate fibrosis lowered the risk of mortality and liver-related progression in a large Spanish cohort of people with HIV/HCV coinfection [1]. The benefit was most pronounced in people with moderate (METAVIR F2) liver fibrosis.

Previous work established the benefits of eradicating HCV in people with advanced fibrosis or cirrhosis. But researchers working with the GESIDA 3606 Study Cohort observed that the clinical benefits of attaining SVR have not been established in people with less advanced fibrosis. They argued that this question is especially relevant for HIV/HCV-coinfected people. The GESIDA team conducted this retrospective analysis to assess the impact of IFN/RBV-induced SVR on mortality, liver-related events, and HIV progression in HIV/HCV-coinfected people with biopsy-proved nonadvanced liver fibrosis.

The study group consists of people with HIV and HCV who began IFN/RBV between January 2000 and January 2008 at 19 clinical centers across Spain. Baseline liver biopsies in all participants had a METAVIR score of F0, F1, or F2. Follow-up continued from the time IFN/RBV stopped until the last study visit, a second course of IFN/RBV, or death.

Among 695 people who met those criteria, 77 (11%) had a METAVIR score of F0, 290 (42%) had F1 fibrosis, 328 (47%) had F2 fibrosis, and 274 (39%) achieved SVR. Most people in the SVR and no-SVR groups (69% and 75%) were men, while CD4 counts averaged 562 and 536. The groups were similar in median age (39.8) and weight (68 kg), proportion with low educational level (62%), proportion of prior injection drug users (83%), and proportion with an undetectable HIV load (66%). The proportion of people with CDC category C disease was lower in the SVR group than in the no-SVR group (16% versus 22%, P < 0.05).

People who attained SVR included a lower proportion with HCV genotype 1 or 4 (44% versus 76%, P < 0.05) and thus a higher proportion with genotype 2 or 3 (56% versus 24%). The SVR group also included a lower proportion with a pretreatment HCV load at or above 500,000 IU/mL (62% versus 76%, P < 0.05) and a lower proportion who drank more than 50 g of alcohol daily (2% versus 6%, P < 0.05). METAVIR fibrosis scores did not differ significantly between people who attained SVR and those who did not.

Three variables predicted SVR: HCV genotype 2 or 3 (odds ratio [OR] 4.24, 95% confidence interval [CI] 2.91 to 6.19), pretreatment HCV load below 500,000 IU/mL (OR 1.88, 95% CI 1.27 to 2.78), and drinking less than 50 g of alcohol daily (OR 4.04, 95% CI 1.11 to 14.8).
Through 96 months of follow-up, cohort members who attained SVR had significantly lower Kaplan-Meier-estimated overall mortality (P = 0.010), liver-related mortality (P = 0.024), liver decompensation (P = 0.010), and liver-related events (which included liver-related death, liver decompensation, hepatocellular carcinoma, and liver transplantation) (P < 0.001).

Among people with an F2 METAVIR score, people who achieved SVR had significantly lower mortality (0.29 versus 1.07 per 100 person-year [py]), liver-related mortality (0.07 versus 0.53 per 100 py), AIDS incidence (0.14 versus 0.69 per 100 py), and liver decompensation rate (0.22 versus 1.31 per 100 py) (P < 0.05 for all differences) than people who did not attain SVR. An analysis focused on people with F2 fibrosis found that those attaining SVR had significantly lower mortality (0.16 versus 1.57 per 100 py), liver-related mortality (0.16 versus 1.05 per 100 py), and liver decompensation rate (0.16 versus 1.85 per 100 py) (P < 0.05 for all differences) than people who did not attain SVR. Among people with a METAVIR score of F0 or F1, these progression rates did not differ significantly between those who attained SVR and those who did not.

Cox regression analysis to determine risk of liver-related events according to METAVIR fibrosis stage adjusted for age, gender, history of injection drug use, CDC clinical category, CD4 count, HCV genotype, and HCV load. In this analysis people who attained SVR with F0 to F2 fibrosis or with F2 fibrosis had almost a 90% lower risk of progression, as indicated in the following list. The group with F0 or F1 fibrosis had about an 80% lower risk of progression, but this difference stopped short of statistical significance:

Progression risk with SVR versus no SVR:
METAVIR F0-F2: adjusted hazard ratio (aHR) 0.13, 95% CI 0.03 to 0.59, P = 0.008
METAVIR F2: aHR 0.11, 95% CI 0.01 to 0.86, P = 0.035
METAVIR F0-F1: aHR 0.21, 95% CI 0.02 to 1.94, P = 0.169

The GESIDA team concluded that "eradication of HCV in HIV/HCV-coinfected patients with nonadvanced liver fibrosis (F0 to F2), and, more specifically, with moderate stages of liver fibrosis (F2), is associated with a reduction in the risk of mortality and liver-related events." They argued that these findings "constitute a strong rationale for considering anti-HCV treatment in this population group, particularly treatment based on the newer and more effective direct antiviral agents."

ReferenceL

1. Berenguer J, Zamora FX, Díez C, et al. Hepatitis C eradication reduces liver decompensation, HIV progression, and death in HIV/HCV-coinfected patients with non-advanced liver fibrosis. 53rd ICAAC. September 10-13, 2013. Denver. Abstract H-1527.

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Hepatitis C Eradication Reduces Liver Decompensation, HIV progression, and Death in HIV/HCV-coinfected Patients with non-Advanced Liver Fibrosis

Continue here to view posters ……

Radiofrequency ablation, hepatic resection similarly safe, effective for small HCC

Provided by Healio

September 17, 2013

Patients with hepatocellular carcinoma of smaller size experienced similar survival and safety outcomes from hepatic resection and radiofrequency ablation in a study presented at the International Liver Cancer Association Annual Conference in Washington, DC.

Researchers evaluated 659 patients who developed hepatocellular carcinoma (HCC) between 1999 and 2007. Patients included 289 who received percutaneous, ultrasound-guided radiofrequency ablation (RFA) while under general anesthesia, and 370 who underwent hepatic resection as initial curative therapy. All nodules were 5 cm in size or smaller.

“Whether RFA is a feasible alternative treatment for small HCC remains controversial,” the researchers wrote. “Thus, instead of a randomized controlled trial, we conducted a propensity analysis to compare the outcomes of RFA versus surgery.”

At 5 years after treatment, survival rates were 65% of RFA recipients and 68% of surgery recipients, while recurrence-free survival rates were 27% and 26%, respectively. The two methods did not differ significantly on Cox proportional hazards analysis, or on propensity analysis incorporating 146 propensity-score-matched pairs from each group. Investigators said patients with poor liver function were more likely to undergo RFA, while patients with highly malignant tumors were more likely undergo resection.

Bleeding into the abdominal cavity occurred in 0.3% of patients who received RFA. Death due to surgery-related complications occurred in 0.5% of resected patients.

“There was no difference in either overall or recurrence-free survival between patients undergoing RFA and those treated surgically,” the researchers concluded. “If appropriate patient selection criteria are applied, RFA under general anesthesia is a safe and effective treatment for small HCC.”

Disclosure: The researchers report no relevant financial disclosures

For more information:

Saito A. P-125: Radiofrequency Ablation Under General Anesthesia Versus Hepatic Resection for Hepatocellular Carcinoma. Presented at: The International Liver Cancer Association Annual Conference 2013; Sept. 13-15, Washington, DC.

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Coffee May Offer Real Benefits to the Liver

Provided by Clinical Care options

Mark S. Sulkowski, MD - 8/13/2013 More from this author

Mixed Realities of Alternative Therapies for Hepatitis
Approximately 50% of patients who have failed initial therapy for hepatitis C take some form of alternative or complementary therapy. In my practice, I’m frequently asked by these and other patients: “What can I do to help my liver?” Most have heard of, have taken, or are taking milk thistle, licorice root, ginseng, schisandra, and/or thymus extract—with milk thistle being the most common. Not all alternative therapies are created equal and there are few randomized controlled trials to guide clinicians seeking answers. For instance, the active ingredient in milk thistle, silymarin, has been evaluated and generally found to provide little or no clinical benefit to the liver. In fact, a recent study found that even at higher-than-usual doses, silymarin failed to reduce HCV RNA or ALT levels more than placebo.

There is, however, a growing body of research supporting a beverage I’d wager a majority of you have enjoyed today: coffee.

The Coffee Alternative
Curiously, patients who will spend up to $30 a day or more for milk thistle and its extracts or ingest unproven therapies of varying quality are skeptical about the idea that drinking coffee can actually be good for you. Real and perceived cardiovascular and other effects of coffee have led many patients to view coffee as “unhealthy.” But the reality is that coffee consumption has been linked to a number of potential benefits – lower risk of diabetes, dementia and, yes, liver disease. Coffee contains more than 1000 compounds; one or more of which is responsible for the benefit that has been linked to coffee intake on liver disease in patients with alcoholic and viral hepatitis. Benefits include decreases in markers of liver disease progression and reductions in the risk for fibrosis and hepatocellular carcinoma.

Epidemiologic studies have suggested that there is a cause and effect associated with coffee intake and its benefits on the liver. These findings are supported by the few randomized controlled trials available. In one study comparing patients infected with hepatitis C, those who drank 3 cups of coffee per day or more received the greatest benefit. In order to maximize the effects of the coffee some (but not all) studies suggest that caffeinated coffee may be better for the liver than decaffeinated coffee. However, it seems that caffeine itself does not appear to have a beneficial effect.

There is also an interesting conundrum. Not just any caffeinated beverage will do. For instance, studies evaluating the effect of green tea – popularly considered a “healthier” source of caffeine – have not shown the benefits associated with filtered, caffeinated coffee. This lack of benefit appears to be true for sources of caffeine other than green tea as well.

Lastly, coffee should ideally be prepared by filtration because filtering removes cafestol and kahweol, two substances found in coffee that may increase serum cholesterol.

Continue reading full article here …..

NIH-funded study suggests brain is hard-wired for chronic pain

For Immediate Release: Tuesday, September 17, 2013

Brain’s white matter may determine susceptibility to chronic pain

The structure of the brain may predict whether a person will suffer chronic low back pain, according to researchers who used brain scans. The results, published in the journal Pain, support the growing idea that the brain plays a critical role in chronic pain, a concept that may lead to changes in the way doctors treat patients. The research was supported by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health.

“We may have found an anatomical marker for chronic pain in the brain,” said Vania Apkarian, Ph.D., a senior author of the study and professor of physiology at Northwestern University Feinberg School of Medicine in Chicago.

Chronic pain affects nearly 100 million Americans and costs the United States up to $635 billion per year to treat. According to the Institute of Medicine, an independent research organization, chronic pain affects a growing number of people.

A Map of Chronic Pain
Scientists used the structure of the brain’s white matter (green lines) to predict whether a subject would recover from low back pain. Red dots represent differences in white matter structure between subjects who recovered and who suffered chronic pain. Courtesy of Apkarian lab, Northwestern University Feinberg School of Medicine.

“Pain is becoming an enormous burden on the public. The U.S. government recently outlined steps to reduce the future burden of pain through broad-ranging efforts, including enhanced research,” said Linda Porter, Ph.D, the pain policy advisor at NINDS and a leader of NIH’s Pain Consortium. “This study is a good example of the kind of innovative research we hope will reduce chronic pain which affects a huge portion of the population.”

Low back pain represents about 28 percent of all causes of pain in the United States; about 23 percent of these patients suffer chronic, or long-term, low back pain.

Scientists have thought the cause of low back pain could be found at the site of injury. However, recent studies suggest that the brain may be more involved with chronic pain.

“Currently we know very little about why some patients suffer chronic low back pain,” said Debra Babcock, M.D., Ph.D., a program director at NINDS. “The earlier we detect pain will become chronic, the better we may be able to treat patients.”

Dr. Apkarian and his colleagues addressed this by scanning the brains of 46 people who had low back pain for about three months before coming to the hospital but who had not had any pain for at least a year before.

The researchers scanned the subjects’ brains and evaluated their pain with doctor’s examinations and questionnaires four times over a period of one year. About half of the subjects recovered at some time during the year; the other half had pain throughout, which the researchers categorized as persistent.

Previously, the Apkarian laboratory showed that the volume of grey matter in the brains of the same subjects who had persistent pain decreased over the same year. Grey matter describes the area of the brain where the central bodies and branched antennae, or dendrites, of nerve cells reside. They also showed that brain activity could be used to predict whether a subject recovered or experienced persistent pain.

In this study, the researchers used a scanning technique called diffusion tensor imaging (DTI) which measures the structure of white matter, the nerve cell wires, or axons, which connect brain cells in different parts of the brain. They found a consistent difference in white matter between the subjects who recovered and the subjects who experienced pain throughout the year.

“Our results suggest that the structure of a person’s brain may predispose one to chronic pain,” said Dr. Apkarian.

In agreement with this idea, the researchers also found that the white matter of subjects who had persistent pain looked similar to a third group of subjects known to suffer from chronic pain. In contrast, the white matter of the subjects who recovered looked similar to that of healthy control subjects.

To test this idea further, the researchers asked whether the white matter differences they saw during the initial brain scans predicted whether the subjects would recover or continue to experience pain. They found white matter brain scans predicted at least 80 percent of the outcomes.

“We were surprised how robust the results were and amazed at how well the brain scans predicted persistence of low back pain,” said Dr. Apkarian. “Prediction is the name of the game for treating chronic pain.”

The nucleus accumbens and the medial prefrontal cortex are two brain regions thought to be involved with pain. Further examination of the brain scans suggests that the white matter structure connecting these brains regions is different between the subjects who recovered and those who had persistent pain.

“Our results support the notion that certain brain networks are involved with chronic pain,” said Dr. Apkarian. “Understanding these networks will help us diagnose chronic pain better and develop more precise treatments.”

This study was supported by a grant from NINDS (NS35115) and an anonymous foundation.

NINDS is the nation’s leading funder of research on the brain and nervous system. The NINDS mission is to reduce the burden of neurological disease – a burden borne by every age group, by every segment of society, by people all over the world.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

NIH...Turning Discovery Into Health^®

References

Mansour et al. “Brain white matter structural properties predict transition to chronic pain” Pain, 154, October 2013, DOI #: 10.1016/j.pain.2013.06.044

For more information about chronic pain, please visit:
http://www.ninds.nih.gov/disorders/chronic_pain/chronic_pain.htm

For more information about NIH’s Pain Consortium, please visit:
http://painconsortium.nih.gov

Source

The regulatory process in Japan for Simeprevir

17-Sep-13 Stockholm, Sweden — Medivir AB (OMX: MVIR) On February 22, 2013 Janssen submitted a regulatory application to the Japanese Ministry of Health & Welfare authorities seeking approval for simeprevir, administered with pegylated interferon (Peg-IFN) and ribavirin (RBV) for the treatment of genotype 1 chronic hepatitis C.

As a part of the regulatory process there has been a closed meeting where simeprevir has been discussed by leading clinicians in Japan. The purpose of the meeting was to evaluate simeprevir and give guidance to the regulatory authorities.

The conclusions from this closed meeting are not officially known to us and Medivir will return with information when the regulatory process allows.

For more information please contact:
Rein Piir, EVP Corporate Affairs & IR
Mobile: +46 708 537 292.

About Medivir
Medivir is an emerging research-based pharmaceutical company focused on infectious diseases. Medivir has world class expertise in polymerase and protease drug targets and drug development which has resulted in a strong infectious disease R&D portfolio. The Company’s key pipeline asset is simeprevir, a novel protease inhibitor in late phase III clinical development for hepatitis C that is being developed in collaboration with Janssen R&D Ireland. Medivir has also a broad product portfolio with prescription pharmaceuticals in the Nordics.

For more information about Medivir AB, please visit the Company’s website: www.medivir.com

Source

BioLineRx Announces Receipt of a Notice of Allowance from USPTO for Patent on Use of BL-8020, an Oral, Interferon-Free Treatment for Hepatitis C

PRESS RELEASE September 17, 2013, 7:19 a.m. ET

- Patent valid until at least 2031 -

JERUSALEM, Sept. 17, 2013 /PRNewswire/ -- BioLineRx Ltd. (NASDAQ:BLRX) (TASE:BLRX), a biopharmaceutical development company, announced today that a Notice of Allowance has been issued by the United States Patent and Trademark Office (USPTO) for BL-8020, an orally available, interferon-free treatment for hepatitis C. The patent covers the use of BL-8020 for treating HCV-infected patients non-responsive to an anti-HCV therapy (patients who failed to achieve a sustained virologic response following treatment). The patent will be valid until at least 2031.

(Logo: http://photos.prnewswire.com/prnh/20130730/630769 )

"We are very pleased to have received a Notice of Allowance from the USPTO for the BL-8020 patent. This is an important milestone in the development of this promising drug candidate," stated Dr. Kinneret Savitsky, Chief Executive Officer of BioLineRx. "HCV induces a chronic infection in more than half of individuals infected with the disease and, depending on the virus genotype, as few as 60% completely recover. In addition, current standard-of-care treatments are lengthy and not well tolerated. As a result, there is a clear need for therapeutics that can increase the effectiveness of existing treatments, especially in patients who have already undergone treatment, but have failed to respond or have relapsed. Based on its pre-clinical results, unique mechanism of action and synergistic effect with other anti-HCV compounds, we are very hopeful that BL-8020 will enhance the effectiveness of other available hepatitis C treatments, thereby significantly improving hepatitis C care. We look forward to the partial results from the Phase 1/2 trial expected towards the beginning of 2014."

BioLineRx is currently conducting a Phase 1/2, open-label study at two sites in France to evaluate the efficacy, safety and tolerability of BL-8020 in patients infected with HCV. The study will include up to 32 HCV-infected patients of any genotype who have previously failed or relapsed following treatment with the standard-of-care. BL-8020 is a proprietary oral, fixed-dose combination treatment composed of Ribavirin and Hydroxychloroquine (HCQ). The primary endpoint of the study is to evaluate the effect of a 16-week combination therapy with Ribavirin and HCQ. The study is specifically designed to allow intra-subject analysis, in order to determine the extent to which HCQ enhances Ribavirin's antiviral activity.

About BL-8020

BL-8020 is a proprietary fixed-dose combination treatment composed of Ribavirin and Hydroxychloroquine (HCQ). Efficacy results in replicon assays, as well as in ex-vivo infected human liver samples, showed a time and dose-dependent inhibitory effect of BL-8020 on HCV replication and infectivity. In addition, a synergistic effect with other anti-HCV agents was observed in these models. This effect on other therapies is likely to increase their potency and reduce the numerous adverse effects often associated with these drugs by reducing their effective doses. BL-8020 targets the infected host cells and inhibits HCV induced autophagy in the host. This unique mechanism of action differentiates BL-8020 from other currently used anti-HCV agents in its potential pan genotypic activity and high genetic barrier to resistance (low susceptibility for drug-resistant mutations to be developed by the virus). BL-8020 was licensed under a worldwide, exclusive agreement from Genoscience, a French company focused on viral disease therapeutics. It was developed as an anti-viral therapy by Professor Philippe Halfon, Co-Founder and President of Genoscience and a world-renowned scientist for his work on HIV, HPV (human papilloma virus causing cervical cancer) and hepatitis.

About Hepatitis C

Hepatitis C infection is a blood-borne infection of the liver caused by the hepatitis C virus (HCV) which becomes chronic in about 85% of cases. According to a 2011 report from Decision Resources, about 180 million people worldwide are chronically infected with HCV. In addition, HCV infection is the leading cause of liver transplantation and is a risk factor for liver cancer. The global hepatitis market was estimated at $6 billion in 2011 and is forecasted to grow to $20 billion by the end of the decade.

About BioLineRx

BioLineRx is a publicly-traded biopharmaceutical development company dedicated to building a portfolio of products for unmet medical needs, as well as those with advantages over currently available therapies. The Company in-licenses novel compounds primarily from academic institutions and biotech companies based in Israel, develops them through pre-clinical and/or clinical stages, and then partners with pharmaceutical companies for advanced clinical development and/or commercialization.

BioLineRx's current portfolio consists of a variety of clinical and pre-clinical projects, including: BL-1040 for prevention of pathological cardiac remodeling following a myocardial infarction, which has been out-licensed to Ikaria Inc. and is in the midst of a pivotal CE-Mark registration trial; BL-5010 for non-surgical removal of skin lesions, which is expected to commence a pivotal CE-mark registration trial in late 2013; BL-8040 for treating acute myeloid leukemia (AML) and other hematological cancers, which is in the midst of a Phase 2 study; and BL-7010 for celiac disease, which is expected to commence a Phase 1/2 study in late 2013.

For more information on BioLineRx, please visit www.biolinerx.com or download the investor relations mobile device app, which allows users access to the Company's SEC documents, press releases, and events. BioLineRx's IR app is available on the iTunes App Store as well as the Google Play Store.

Various statements in this release concerning BioLineRx's future expectations, including specifically those related to the development and commercialization of BL-8020, constitute "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. These statements include words such as "may," "expects," "anticipates," "believes," and "intends," and describe opinions about future events. These forward-looking statements involve known and unknown risks and uncertainties that may cause the actual results, performance or achievements of BioLineRx to be materially different from any future results, performance or achievements expressed or implied by such forward-looking statements. Some of these risks are: changes in relationships with collaborators; the impact of competitive products and technological changes; risks relating to the development of new products; and the ability to implement technological improvements. These and other factors are more fully discussed in the "Risk Factors" section of BioLineRx's most recent annual report on Form 20-F filed with the Securities and Exchange Commission on March 12, 2013. In addition, any forward-looking statements represent BioLineRx's views only as of the date of this release and should not be relied upon as representing its views as of any subsequent date. BioLineRx does not assume any obligation to update any forward-looking statements unless required by law.

Contact:

KCSA Strategic Communications

Garth Russell / Todd Fromer

+1 212-896-1250 / +1 212-896-1215

grussell@kcsa.com / tfromer@kcsa.com

or

Tsipi Haitovsky

Public Relations

+972-3-6240871

tsipih@netvision.net.il

SOURCE BioLineRx Ltd.

/Web site: http://www.biolinerx.com

Source

'Quad' PIll OK for Older HIV Patients

Published: Sep 15, 2013 | Updated: Sep 16, 2013

By Michael Smith, North American Correspondent, MedPage Today

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Action Points

• This study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
• A four-drug pill quad pill (containing elvitegravir, cobicistat, emtricitabine, and tenofovir) for HIV works as well in older patients as it does in those under 50.
• Note that the older patients (50 and 0ver) taking the quad pill had significantly less dizziness and fewer abnormal dreams compared to those getting efavirenz, emtricitabine, and tenofovir.

DENVER -- A four-drug "quad" pill for HIV works as well in older patients as it does in those under 50, a researcher said.

The quad pill (approved last year and marketed as Stribild) has been shown in several clinical trials to have equivalent efficacy and safety to major first-line HIV regimens, according to Joel Gallant, MD, of the Southwest CARE Center in Santa Fe.

But as the HIV-positive population ages, it becomes important to study the efficacy and safety of medications in older patients specifically, he argued here at the annual Interscience Conference on Anti-Microbial Agents and Chemotherapy.

To address the issue, the authors analyzed two randomized phase III clinical trials in treatment-naïve patients divided by age -- under 50 or 50 and over.

In one of the two trials, the quad pill (containing elvitegravir, cobicistat, emtricitabine, and tenofovir) was compared with the single-pill combination of efavirenz, emtricitabine, and tenofovir (Atripla).

In the second, the quad was compared with boosted atazanavir (Reyataz) and the single-pill combination of emtricitabine and tenofovir (Truvada).

In both cases, efficacy, defined as the ability of the regimen to control viral replication, was similar after 96 weeks of therapy -- 84% and 83%, respectively, for the quad and 82% in both studies for the comparator regimen.

In both studies, tolerability was slightly better for the quad, Gallant noted.

For this analysis, Gallant and colleagues combined the efficacy and safety data from both studies, but compared how older patients stacked up against their younger counterparts.

The proportion of men 50 or older ranged from 14% to 16% in the four original study arms, Gallant said.

For those 50 and older in the quad-Atripla study, efficacy was identical at 96 weeks at 82%. By comparison, the quad pill did slightly better in those under 50 -- 85% versus 81% -- but the difference was not significant.

Results were similar in the other study -- 82% and 81% for those under 50 and 90% in both arms for those 50 and older.

Over the 2 years of the studies, only two patients developed resistance, Gallant noted.

In both age groups, treatment led to a recovery of the immune response that was slightly blunted among those 50 and older but did not differ between treatment arms.

On the adverse events front, the older patients taking the quad:

• Had significantly less dizziness and fewer abnormal dreams compared to those getting Atripla.
• Had an early increase in serum creatinine that stabilized through week 96, was greater than with Atripla, but similar to that experienced by patients on atazanavir/emtricitabine/tenofovir.
• Had similar median increases in lipid parameters to those taking the other comparator regimens.

The study adds to the "comfort level" of clinicians prescribing the quad pill to older patients, commented Joseph Eron, MD, of the University of North Carolina Chapel Hill, who was not involved in the study but who co-moderated the session at which the data was presented.

"You didn't see any peculiar toxicities among the older group," Eron told MedPage Today. "It was reassuring."

It's also gratifying that the analysis could be done at all, Eron said, adding that "it's good to see that we have enough older patients to do the study."

The study was supported by Gilead Sciences. Gallant reported financial links with Bristol-Myers Squibb, Gilead Sciences, Janssen Therapeutics, Merck and Co, and Takara Bio. Several authors are employees of Gilead.

Eron previously disclosed financial relationships with Bristol-Myers Squibb, GlaxoSmithKline, Merck, Tibotec, and ViiV Healthcare.

Primary source: Interscience Conference on Anti-Microbial Agents and Chemotherapy
Source reference: Gallant JE, et al "Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF (E/C/F/TDF) demonstrates comparable efficacy and favorable tolerability to efavirenz (EFV)/FTC/TDF and to ritonavir-boosted atazanavir (ATV+RTV) plus FTC/TDF in subjects 50 years and older at week 96" ICAAC 2013; Abstract H-1459.

Source

Celsion Corporation's ThermoDox® HEAT Study Findings Reviewed at the International Liver Cancer Association (ILCA) 2013 Annual Conference in Washington, D.C. on September 14, 2013

Updated Overall Survival in Large Subgroup Continues to Show Positive Clinical Benefit

Company Sponsors Symposium on Directions in Early-Intermediate HCC

LAWRENCEVILLE, N.J., Sept. 16, 2013 /PRNewswire/ -- Celsion Corporation (NASDAQ: CLSN) announced today that Ronnie T.P. Poon, MD, MS, PhD, FRCS (Edin), FACS, Professor of Surgery at the University of Hong Kong and Lead Asia Pacific Principal Investigator for Celsion's Phase III HEAT Study of ThermoDox® in hepatocellular carcinoma (HCC) reviewed the official clinical trial results from the HEAT Study including findings from the HEAT Study post-hoc analysis at the International Liver Cancer Association 7^th Annual Conference held on September 13-15, 2013 in Washington D.C.  Following Professor Poon's presentation on September 14, 2013, the Company sponsored a symposium of leading liver cancer experts to discuss new directions in the treatment of early-intermediate HCC.

Professor Poon's oral presentation, titled "Phase 3 Randomized, Double-Blind, Dummy Controlled Trial of Radiofrequency Ablation (RFA) + Lyso-Thermosensitive Liposomal Doxorubicin for Hepatocellular Carcinoma (HCC) Lesions 3-7 cm," was held on September 14, 2013 at 12:00 p.m. (local time) during the Plenary Session.  Professor Poon's presentation also included the most recent Overall Survival data from the HEAT Study post-hoc analysis which continues to suggest positive progression-free survival (PFS) and Overall Survival (OS) in ThermoDox® treated patients when heating cycles from the radiofrequency ablation (RFA) procedure were optimized.

The data from the HEAT Study post-hoc analysis presented by Professor Poon demonstrate that ThermoDox® markedly improves Overall Survival, when compared to the control group, in patients if their lesions undergo RFA for 45 minutes or more.  These findings apply to single HCC lesions (63% of the HEAT Study population) from both size cohorts of the HEAT Study (3-5 cm and 5-7 cm) and represent a subgroup of approximately 300 patients (42% of the patients in the HEAT Study).

• In the patient subgroup treated in the ThermoDox® arm whose RFA procedure lasted longer than 45 minutes and was completed within 90 minutes (40% of single lesion patients) Overall Survival improved by 71% (Hazard Ratio of 0.585) when compared to the control arm of RFA treatment only.
• In the patient subgroup treated in the ThermoDox® arm whose RFA procedure lasted longer than 90 minutes (23% of single lesion patients), Overall Survival improved by similar 71% (Hazard Ratio of 0.584) when compared to the control arm of RFA treatment only.
• When combined, these two subgroups show clinical results that indicate a 61% improvement in Overall Survival, a Hazard Ratio of 0.623 and a P-value = 0.058.
• In contrast, the patient subgroup treated with ThermoDox® whose RFA procedure lasted less than 45 minutes in duration (37% of single lesion patients) indicated that the control arm had a slightly improved Overall Survival benefit when compared to the ThermoDox® arm.
• The Hazard Ratio reported above should be viewed with caution since they are not statistically significant and the HEAT Study has not reached its median point for Overall Survival analysis.  Celsion continues to follow all patients in the HEAT Study to the secondary endpoint, Overall Survival, and will update the subgroup analysis based on RFA heating duration.

Celsion also sponsored a symposium in conjunction with the ILCA conference moderated by Professor Riccardo Lencioni, MD, FSIR, EBIR, the Director of the Division of Diagnostic Imaging and Intervention at Pisa University School of Medicine in Italy.   Participants included Professor Josep Llovet, MD, PhD, Professor of Medicine and Director, Mount Sinai Liver Cancer Program, Mount Sinai School of Medicine; Ghassan K. Abou-Alfa MD, PhD, Associate Attending Memorial Sloan-Kettering Cancer Center, New York, NY, Associate Professor, Weill Medical College at Cornell University, New York, NY, and Associate Professor, Gastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY; and Professor Ronnie T.P. Poon, MD, PhD.  The discussion focused on new developments in the treatment of early-intermediate HCC including the updated data from the Company's HEAT Study post-hoc analysis as well as computer modeling with supplementary preclinical animal studies supporting the relationship between heating duration and clinical outcomes.

• Results from a finite element method model that simulates temperature, perfusion contours with RFA treatments and allow prediction of drug deposition contour maps with the combined use of RFA and ThermoDox®, show a direct correlation with heating time and amount of drug deposited to the tumor margin, where both adequate heat and tissue perfusion exist.
• Results from recently completed large animal studies (21 subject porcine study) demonstrate that longer RFA heating (dwell) time results in higher local tissue concentrations of ThermoDox® in the surrounding ablation zone.  

Professor Riccardo A. Lencioni commented, "After reviewing the complete and subgroup analysis of the Phase III HEAT Study as well as the recently completed porcine study, I am convinced ThermoDox® demonstrates clinical activity in a highly responsive population of single lesion patients.  The duration of heat from the RFA procedure is an important factor in a successful clinical outcome when combined with ThermoDox® as demonstrated by the growing body of clinical and non-clinical data generated by the Company.  These findings build a solid scientific foundation of understanding that increased perfusion and longer heating duration are key factors for ensuring that the heat-sensitive liposomes are activated to deposit high concentrations of doxorubicin in the tumor and the surrounding liver tissue."

ILCA has selected the HEAT Study presentation to be webcast as part of an online educational program of the ILCA 2013 Annual Conference.  Professor Poon's presentation will also be available on Celsion's website at http://investor.celsion.com/events.cfm.

The International Liver Cancer Association is the only international organization devoted exclusively to liver cancer research for experts from all related disciplines – medical, interventional and surgical oncology as well as hepatology.  ILCA's Executive Committee consists of Dr. Josep M. Llovet (President); Professor Riccardo Lencioni and Dr. Morris Sherman.  Celsion notes that Professors Lencioni and Poon and Dr. Sherman are principal investigators on the HEAT Study.

About Celsion Corporation

Celsion is dedicated to the development and commercialization of innovative cancer drugs, including tumor-targeting treatments using focused heat energy in combination with heat-activated liposomal drug technology.  Celsion has research, license or commercialization agreements with leading institutions, including the National Institutes of Health, Duke University Medical Center, University of Hong Kong, the University of Pisa, the UCLA Department of Medicine, the Kyungpook National University Hospital, the Beijing Cancer Hospital and the University of Oxford.  For more information on Celsion, visit our website: http://www.celsion.com.

Celsion wishes to inform readers that forward-looking statements in this release are made pursuant to the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995.  Readers are cautioned that such forward-looking statements involve risks and uncertainties including, without limitation, unforeseen changes in the course of research and development activities and in clinical trials; the significant expense, time, and risk of failure of conducting clinical trials; HEAT Study data is subject to further verification and review by the HEAT Study Data Management Committee; the need for Celsion to evaluate its future development plans; termination of the Technology Development Contract or collaboration between Celsion and HISUN at any time; possible acquisitions or licenses of other technologies, assets or businesses or the possible failure to make such acquisitions or licenses; possible actions by customers, suppliers, competitors, regulatory authorities; and other risks detailed from time to time in the Celsion 's periodic reports and prospectuses filed with the Securities and Exchange Commission.  Celsion assumes no obligation to update or supplement forward-looking statements that become untrue because of subsequent events, new information or otherwise.

Investor Contact
Jeffrey W. Church
Senior Vice President and
Chief Financial Officer
609-482-2455
jchurch@celsion.com

SOURCE Celsion Corporation

Source

New Hope for H.I.V. Vaccine

Ed Jones/Agence France-Presse — Getty Images

A new vaccine tested in rhesus monkeys generated a muted, long-lasting immune response to the simian version of H.I.V.

By DONALD G. McNEIL Jr.

Published: September 16, 2013

“Kafkaesque” is not a word normally used to describe immune responses, but it’s how Dr. Louis J. Picker described what his experimental vaccine did to his rhesus monkeys: “It’s like their T-cells were turned into the East German secret police, hunting down infected cells until there were none left.”

Recent work by Dr. Picker, a vaccine expert at Oregon Health & Science University, has shaken up the long, frustrating search for an AIDS vaccine. His latest study, published in Nature last week, has scientists scratching their heads, wondering if it might open up a new avenue for research.

Dr. Picker tested his vaccine in 16 monkeys who were then infected with simian immunodeficiency virus, a close relative of H.I.V., which normally would have sent them spiraling rapidly down to a miserable death. The experimental vaccine protected only nine of them, but it also did something never seen before: these monkeys slowly “cleared” the virus and now appear to be cured. “Three years later, you can’t tell them from other monkeys,” Dr. Picker said.

Dr. Anthony S. Fauci, the head of the National Institute for Allergy and Infectious Diseases, said the effect was “unique.”

And Dr. Barton F. Haynes, the director of the Human Vaccine Institute at Duke University’s medical school, said it was “potentially extremely important to understand how this happened.”

Scientists often test ideas for potential AIDS vaccines by creating similar ones against S.I.V. Never before has one eliminated an existing infection. In that sense, the effect of Dr. Picker’s vaccine was less like that of a measles or flu shot and more like that of the AIDS cures used in two famous cases, known as the Berlin patient and the Mississippi baby.

The Berlin patient, Timothy Ray Brown, was infected with H.I.V. and cured only by obliterating his immune system to defeat his leukemia, and then injecting bone marrow from a donor with a rare H.I.V.-blocking mutation. The unidentified baby was born to an infected mother in Mississippi and apparently infected with H.I.V., but then cured with early and large doses of antiretroviral drugs.

Both now appear to have no H.I.V. lurking deep in their bodies, but it is impossible to be sure because not every bit of their tissue can be tested.

Because he works with monkeys, Dr. Picker was able to do something that would be unthinkable with human patients — necropsy them, grind up every organ and take 240 samples from each to be sure that they harbored no hidden virus.

Making vaccines by simply weakening the virus that causes AIDS has failed because the virus mutates a hundred times faster than even the fast-mutating flu virus. In Dr. Picker’s vaccine, S.I.V. genes are fused to those of another virus, the cytomegalovirus. (The name means “big cell,” and it is in the herpes family but different from its relatives that cause lip and genital sores, chickenpox and shingles.)

H.I.V. fusion has been tried with adenoviruses and others, but cytomegalovirus seems to work better. It’s not entirely clear why, but one theory is that cytomegalovirus has a very long history of infecting primates — so much so that 100 percent of monkeys and about 80 percent of humans get it in their lifetimes.

Therefore, we primates have adapted to it. Although the virus can be lethal to fetuses and to those with immune systems suppressed by AIDS or transplant drugs, in most victims it causes no symptoms.

The body responds to cytomegalovirus more slowly and calmly than it does, for example, to a flu.

As in any infection, the thymus gland generates new white blood cells called T cells — in this case, CD8 hunter-killer cells — primed to target the specific virus. But in the case of Dr. Picker’s vaccine, those cells stay in an unusual “half-alert” state. A full-blown immune response eventually exhausts itself, and can even be dangerous. For example, the rare humans who catch H5N1 bird flu often die of the immune response itself; they drown in the flood of CD8s and other would-be saviors pouring into the lung tissue, spoiling for a fight.

That “half-alert” state is the “Kafkaesque” element: unactivated CD8s wander around aimlessly, while fully activated ones behave like storm troopers. But the half-activated CD8s persist in tissues, eliminating their targets quietly without triggering inflammation or even a mild fever.

When S.I.V. genes are fused to the cytomegalovirus spine, the CD8s kill S.I.V.-infected cells too.

Since it protected only some monkeys, the new technique might be best used in combination approaches. For example, Dr. Fauci said, it could be given with a vaccine that generates antibodies against H.I.V. “and maybe eliminate the cells that sneak past the antibody shield.”

Alternatively, the vaccine might be given to infected patients who are on antiretroviral drugs to see if it can “mop up” lingering reservoirs of virus.

It should take up to three years to get a human version ready for trials, Dr. Picker estimated.

“Now the outstanding question is, ‘Why only half?’ ” said Dr. Mike McCune, an AIDS researcher at the University of California, San Francisco, referring to the monkeys who were protected in Dr. Picker’s trial.

Too often, AIDS advances that work in lots of monkeys don’t work in many humans.

“Not all monkeys are the same,” Dr. McCune said. “They’re not as inbred as mice, but they’re sometimes from the same families, they get the same diets... Who knows what will happen if this goes into humans?”

Source

How Can Chinese Medicine Help Me? - A patient consultation with Dr. Misha Cohen

   

How Can Chinese Medicine Help Me? - A patient consultation with Dr. Misha Cohen from Caring Ambassadors Program on Vimeo.

FDA Antiviral Drugs Advisory Committee set for October 24 to consider HCV New Drug Application (NDA) 205123, Simeprevir

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration

Food and Drug Administration 
[Docket No. FDA-2013-N-0001]
Antiviral Drugs Advisory Committee; Notice of Meeting
AGENCY:  Food and Drug Administration, HHS.
ACTION:  Notice.

This notice announces a forthcoming meeting of a public advisory committee of the Food and Drug Administration (FDA).  The meeting will be open to the public.

Name of Committee: Antiviral Drugs Advisory Committee.

General Function of the Committee: To provide advice and recommendations to the Agency on FDA's regulatory issues.

Date and Time: The meeting will be held on October 24, 2013, from 8 a.m. to 5 p.m.

Location: Sheraton Silver Spring Hotel, Cypress Ballroom, 8777 Georgia Ave., Silver Spring, MD.  The hotel phone number is 301-589-0800.

Contact Person: Karen Abraham-Burrell, Center for Drug Evaluation and Research,
Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 31, rm. 2417, Silver Spring,
MD 20993-0002, 301-796-9001, FAX: 301-847-8533, email: AVAC@fda.hhs.gov, or FDA
Advisory Committee Information Line, 1-800-741-8138 (301-443-0572 in the Washington, DC
area). 

A notice in the Federal Register about last minute modifications that impact a previously announced advisory committee meeting cannot always be published quickly enough to provide
timely notice.  Therefore, you should always check the Agency's Web site at
http://www.fda.gov/AdvisoryCommittees/default.htm and scroll down to the appropriate advisory committee meeting link, or call the advisory committee information line to learn about possible modifications before coming to the meeting.

Agenda:  The committee will discuss new drug application (NDA) 205123, simeprevir (a hepatitis C virus protease inhibitor), manufactured by Janssen Pharmaceutical Co., with a
proposed indication for the treatment of chronic hepatitis C genotype 1 infection, in combination
with peginterferon alfa and ribavirin (two medicines approved to treat chronic hepatitis C) in
adult patients with compensated liver disease (including cirrhosis) who are treatment-naïve or
who have failed previous interferon therapy (pegylated or non-pegylated) with or without ribavirin. Compensated liver disease is a stage in which the liver is damaged but maintains ability to function. 

FDA intends to make background material available to the public no later than 2 business
days before the meeting.  If FDA is unable to post the background material on its Web site prior to the meeting, the background material will be made publicly available at the location of the advisory committee meeting, and the background material will be posted on FDA's Web site after the meeting.  Background material is available at
http://www.fda.gov/AdvisoryCommittees/Calendar/default.htm. Scroll down to the appropriate
advisory committee meeting link.

Procedure:  Interested persons may present data, information, or views, orally or in writing, on issues pending before the committee.  Written submissions may be made to the contact person on or before October 9, 2013.  Oral presentations from the public will be scheduled between approximately 1 p.m. and 2 p.m.  Those individuals interested in making formal oral presentations should notify the contact person and submit a brief statement of the general nature of the evidence or arguments they wish to present, the names and addresses of proposed participants, and an indication of the approximate time requested to make their presentation on or before October 1, 2013.  Time allotted for each presentation may be limited.  If the number of registrants requesting to speak is greater than can be reasonably accommodated during the scheduled open public hearing session, FDA may conduct a lottery to determine the speakers for the scheduled open public hearing session.  The contact person will notify interested persons regarding their request to speak by October 2, 2013.

Persons attending FDA's advisory committee meetings are advised that the Agency is not
responsible for providing access to electrical outlets.

FDA welcomes the attendance of the public at its advisory committee meetings and will
make every effort to accommodate persons with physical disabilities or special needs. If you
require special accommodations due to a disability, please contact Karen Abraham-Burrell at
least 7 days in advance of the meeting.

FDA is committed to the orderly conduct of its advisory committee meetings.  Please visit our Web site at http://www.fda.gov/AdvisoryCommittees/AboutAdvisoryCommittees/ucm111462.htm for
procedures on public conduct during advisory committee meetings.

Notice of this meeting is given under the Federal Advisory Committee Act (5 U.S.C. app.

Dated:  September 11, 2013. 
Jill Hartzler Warner, Acting Associate Commissioner for Special Medical Programs.   
[FR Doc. 2013-22546 Filed 09/16/2013 at 8:45 am; Publication Date: 09/17/2013]

Screen All Boomers for Hep C? Two Docs Disagree

Medscape Family Medicine > Roundtable in Primary Care

Robert W. Morrow, MD, Charles P. Vega, MD

Sep 16, 2013

Editor's Note: The Centers for Disease Control and Prevention (CDC) and the US Preventive Services Task Force (USPSTF) have recommended that all baby boomers (those born between 1945 and 1965) should be screened for hepatitis C virus (HCV). We asked Charles P. Vega, MD, and Robert W. Morrow, MD, Medscape family physician advisors, how realistic these recommendations are in primary care practice. We received 2 different opinions.^[1,2]

Dr. Vega: Screening These Adults Is Important, and I'm On Board

The age range described in the recommendations fit the majority of my patient panel: those who have an average of 6 chronic conditions. Getting health maintenance completed can be a struggle, given other competing priorities. So I was highly skeptical about checking hepatitis C status on these sweet older adults.

However, on examining the evidence, this is the generation that bears a disproportionate burden of HCV infection, morbidity, and mortality. Moreover, trials of anti-HCV treatment did include, if not focus on, older adults. These are the studies that demonstrated that sustained virologic response improved cancer and mortality outcomes.

Why hadn't I learned this stuff before? Who knows. But I'm on board. One-time screening is more than reasonable and will save lives.

However, the overall incidence of HCV infection appears to have declined over the past 10 years. This screening recommendation is for a limited time only. (Now, there's a potential new marketing gimmick for the USPSTF!) We should keep that in mind moving forward.

Dr. Morrow: Where's the Evidence Supporting Benefits vs Risks of Screening?

Like most of the subjects raised in these roundtables, this one has some substance that was not initially apparent.

Generally, we screen for a disease when the benefit exceeds the risk. In other words, if we randomize the population to those screened and unscreened, the unscreened group should do worse than the screened group using some objective, patient-centered measure, even if that is the quality-adjusted life-year.

As a disease becomes less likely or prevalent, false-positive findings become more common than true-positives.

For example, a polymerase chain reaction test with high sensitivity and specificity might still yield a rather high false-positive result. We see false-positives with Pap tests for women older than 40 years, and for purified protein derivative tests in general; in the first case, as women get older cervical cancer becomes very rare, and in the other case, tuberculosis is less present in the general population.

A false-positive rate of 1/1000 seems small until after the first million studied!

OK, we don't have the information that the tested group does better than the untested group in measures important to patients. So is this an emergency, and therefore we can't wait for a patient-centered study? We need to see the numbers of measures important to patients. Do screened patients die later, transmit less disease to bystanders, or have less disability compared with unscreened people? Right now, that is assumed but not known.

Aside from fatigue for months, I have several patients in my practice with injury from HCV treatment, including hyperthyroidism. One patient had to have surgery for refractory hyperthyroidism after radioactive iodine, and now has lost much of her voice due to injury during intubation.

Regardless, anecdotes suck, so where are the numbers that are patient-centered, not pharma-centered?

I suppose if we had a real healthcare system, we could conduct this study in a few months of analysis of population databases. Hello, Kaiser, what do you know? Until then, did your laboratory have a new technician who made a methods error that resulted in false-positives, owing to contamination of a hypersensitive test? I think that's why I see several inexplicable HPV-positive tests in women older than 50 years, which go away on repeat tests -- and yes, I don't order the test, but laboratories often run HPV tests without a request.

Show me the analysis, so I can understand why this expensive and not necessarily faultless test -- which can lead to treatments that are expensive and not necessarily faultless or successful -- is truly patient-centered. Until then, we should spend the funds on prevention strategies that work, such as needle exchanges and careful histories.

Dr. Vega: False-Positives Are Rare, and We Can't Wait for Studies

Bob is completely accurate in pointing out how every screening test has both a downside and a potential benefit. In fact, he lists some screening tests, such as for tuberculosis in the general population, that do not make sense because the potential harms outweigh the advantages of testing.

HCV screening for this specific age population is not in that class of testing. The prevalence of HCV among persons born between 1945 and 1965 is 3.25%, which sounds small until one realizes that this represents approximately three quarters of cases of chronic HCV infection in the United States. The infection is underrecognized by clinicians treating these patients, and that is a huge contributor to the overall morbidity and mortality of HCV.

With regard to the potential harms of screening, false-positive HCV antibody tests are extremely rare. New-generation anti-HCV screening yields specificity levels above 99%. Advancements in the evaluation of patients with chronic HCV infection have reduced the need for liver biopsy, which incurred the majority of major complications in the work-up of HCV. Complications from HCV treatment are common, but serious complications are rare. The reductions in the risks for cirrhosis and death with HCV treatment generally outweigh the risks of therapy.

It would be wonderful to have a randomized screening trial with thousands of participants to fully evaluate screening for HCV. But Bob knows that such a study is impractical and won't ever happen. First, it will require years to even set up the research, and many, many more to complete it. Remember that we didn't well understand the basic natural history of chronic HCV infection until study cohorts were followed for decades. Persons born between 1945 and 1965 simply do not have that kind of time to wait.

To respond to another couple issues, screening for HCV only works if patients found to be positive can be quickly referred for further evaluation and therapy. Otherwise, it is a waste of healthcare resources that may be better used elsewhere.

Regarding the timing of HCV screening: Between regular blood testing for the diabetes, hyperlipidemia, and assorted other chronic illnesses common among my middle-age and older adult patients, I don't think it will be a challenge to recommend an anti-HCV antibody test at some point. Simple decision-support software can facilitate reminders regarding such screening. We have had strong success in our practice in using this strategy to implement universal screening for HIV infection.

Dr. Morrow: Forget RCTs; Look at Large Data Sets

Thanks for your thoughtful comments, Charles.

I am certainly not going to joust with the epidemiology folks at the CDC, but a different number for prevalence among blood donors from 2010 shows a falling rate of HCV antibody prevalence by the less specific test methods, down to 0.072%.^[3]

My general sense is that we have many ways of estimating the expected rates of transmission and liver failure, and because prior transmission was likely owing to sharing of needles and blood transfusions, we do have good preventive measures.

Prospective randomized controlled trials (RCTs) are but one of the methods to analyze risk vs benefits, and often not the best. Could someone step forward and look at these numbers in large data sets systematically before embarking on a campaign?

As an aside, RCTs to a large measure have gotten us into the mess in which you look for answers to clinical questions in the research literature, and questions that are not answered are found far more commonly using this research method, largely because of the linear nature of the process. If you look at A to B, do you get C more commonly than by chance?

In truth, modern analytics, such as Bayesian approaches, are far more predictive than frequentist methods alone. This is simply to say that someone should be funded to look at whether screening large groups of baby boomers for HCV would lead to predictably better outcomes that matter to patients. Yes, indeed, this can be done with many different large data sets using contemporary analytic methods (but please don't ask this community doc for the details!). Think about how Google tells us about traffic on the highways by looking at the number of cell phones and how fast they are travelling and mapping this to the roadways: instantly and clearly, but indirectly.

From my seat in my family medicine office, as well as an educator: We are told not to screen for domestic violence due to lack of outcomes evidence, and not to screen for gun ownership due to politics, and not to screen for chronic alcoholism (only unsafe behaviors) due to difficulty in treatment. We don't screen for Helicobacter pylori. We don't screen men for Chlamydia and gonorrhea.

Why hepatitis C, and why now?

Dr. Vega: It's Time to Screen Now

Good points. I'd just add that Bob is right: The prevalence of HCV is falling, and this may be due to greater public knowledge and interventions to prevent bloodborne transmission. But the more advanced statistical analyses on screening for HCV has been done, and one study showed that age-based screening was actually more cost-effective than screening on the basis of risk factors.^[4] At the end of the day, the screening is imperative now because these older adults are in a time window when screening and treatment should add substantially more years of quality living. That window will not stay open forever, and we as primary care physicians need to understand when it is getting ready to close.

The news that HCV treatment is simplifying and may eventually move to the primary care office should only add to the weight of this recommendation. But that's a topic for a different time.

References

1. Garcia J. Hepatitis C: USPSTF recommends all baby boomers be screened. Medscape. June 24, 2013. http://www.medscape.com/viewarticle/806836 Accessed September 5, 2013.

2. Teo CG. Testing for hepatitis C: new guidance. Medscape. July 29, 2013. http://www.medscape.com/viewarticle/808327 Accessed September 5, 2013.

3. Murphy EL, Fang J, Tu Y, et al. Hepatitis C virus prevalence and clearance among US blood donors, 2006-2007: associations with birth cohort, multiple pregnancies, and body mass index. J Infect Dis. 2010;202:576-584. Abstract

4. Liu S, Cipriano LE, Holodniy M, Goldhaber-Fiebert JD. Cost-effectiveness analysis of risk-factor guided and birth-cohort screening for chronic hepatitis C infection in the United States. PLoS One. 2013;8:e58975.

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Three Students Got Kicked Out Of An Arkansas Public School Because They Might Be HIV-Positive

CREDIT: The Stigma Project

By Tara Culp-Ressler on September 16, 2013 at 8:59 am

A public school district in Arkansas has removed three siblings from school because administrators suspect they may be infected with HIV, according to a local disability rights organization. Under the Americans with Disabilities Act, public schools may not ban children simply based on their HIV status.

The three siblings — two of whom have disabilities — are living with a foster family and attending the Pea Ridge Public School District. But school district officials recently found documentation that suggested the birth mother and one of the kids are both HIV-positive, and told the foster family that none of the children could return to school until they provided proof that they don’t have the virus. When the kids were sent to school the next day anyway, they were “set aside until the foster parents picked them up,” according to a local news outlet.

The Disability Rights Center of Arkansas is accusing the school district of illegally discriminating against the children. They say that school officials have no right to demand medical testing at whim — particularly since, even if the children did test positive for HIV, they would still have the right to attend public school.

“The fact that the foster families have to provide documentation that the children are HIV negative before entering the school is unlawful and immoral,” the group said in a statement last week. “It stigmatizes individuals with disabilities — or their ‘perceived’ disabilities, as there is no indication these individuals have HIV. There is only an unlawful fear that they do.”

The Disability Rights Center is fighting to ensure that the three kids will be placed back in their school. The superintendent of the Pea Ridge district has declined to offer a statement on the controversy, but has indicated the school sought legal counsel before making their decision.

Last year, a private school in Pennsylvania sparked widespread protests after denying admission to an HIV-positive boy. Advocates pointed out that children shouldn’t be denied education opportunities simply because they have HIV. The school eventually reversed its decision after a legal battle with the U.S. Department of Justice, and agreed to provide staff with additional HIV sensitivity training.

Despite significant medical advances that help HIV-positive Americans live increasingly longer and healthier lives, many people still have widespread misconceptions about how the virus is actually spread. That lack of education has contributed to a pervasive stigma surrounding HIV — and a reluctance to integrate HIV-positive individuals with other people who don’t have the virus. Ultimately, that type of stigmatization only helps maintains the epidemic by hampering HIV prevention and outreach efforts.

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