Showing posts with label 2014 Conference on Retroviruses and Opportunistic Infections (CROI). Show all posts
Showing posts with label 2014 Conference on Retroviruses and Opportunistic Infections (CROI). Show all posts

Monday, April 21, 2014

HCV Next - A Conversation with Douglas T. Dieterich, MD

The following articles appeared in the March/April 2014 print edition of  HCV Next at Healio.

Editorial
Introducing our Chief Medical Editors

In this issue, you will read an in-depth cover story with expert opinion on the controversial costs of care surrounding implementation of the new approved direct-acting antiviral therapies. The feature article explores the debate between risk-based and universal HCV screening recommendations for baby boomers. HCV Next Editorial Board member Catherine T. Frenette, MD, and colleagues present an interesting Case Challenge about a patient with unique adverse events after receiving interferon therapy; Douglas T. Dieterich, MD, answers 5 questions about his life in and out of the office; and three HCV Next Editorial Board members provide their take on the most interesting news from CROI 2014.


5 Questions
A Conversation with Douglas T. Dieterich, MD
In this issue, HCV Next asks five questions of Douglas T. Dieterich, MD, professor of medicine in the division of liver diseases and director of continuing medical education at Icahn School of Medicine at Mount Sinai in New York. He maintains a triple appointment in the divisions of liver disease, gastroenterology and infectious diseases.

Case Challenges
An Interesting Case of Inclusion Body Myositis after 48-Week Treatment Course

Andrea Scherschel, MSN, FNP; William B. Minteer, BS; Catherine T. Frenette, MD
A 64-year-old male presents to the gastroenterology/hepatology clinic with chief complaints that included increased shortness of breath since stopping his interferon therapy, progressive lower-extremity weakness and dysphagia.

Cover Stories
DAA is $1,000 a pill; SVR is priceless 
The Price of a Cure
 
The new generation of direct-acting antiviral agents for the treatment of hepatitis C virus promise a potential cure for an estimated 3 million infected Americans, but also promise to come with a high price.


The therapies are making headlines in both the health care community and the mainstream media, largely for three reasons: the drugs’ unprecedented efficacy, attractive adverse event profiles and cost. Although recently approved drugs such as sofosbuvir (Sovaldi, Gilead Sciences) and simeprevir (Olysio, Janssen Therapeutics) have been hailed as groundbreaking therapies with high sustained virologic response rates, the costs are under scrutiny.


A Collaboration for Improved Care

Ira M. Jacobson, MD; Michael S. Saag, MD
Hepatitis C is a multi-faceted disease, with coinfections and rare comorbidities seen in patients that have necessitated a more collaborative approach to care. As each progressive stage of disease often requires the expertise of a different specialist, increased communication and the sharing of knowledge between gastroenterologists, hepatologists, and infectious disease specialists is the optimal approach to comprehensive HCV care. 


Feature
Calling All Baby Boomers: HCV Screening Slowly Takes Hold

“A one-time blood test for hepatitis C should be on every baby boomer’s medical checklist,” CDC director Thomas R. Frieden, MD, MPH, stated in a recent press release. “The new recommendations can protect the health of an entire generation of Americans and save thousands of lives.”

HCV Rx
Simeprevir: A New NS3/4A Protease Inhibitor

Leah Molloy, PharmD
Several novel direct-acting antivirals are currently under development in the rapidly evolving field of hepatitis C virus treatment. The newest protease inhibitor, simeprevir, was approved for the treatment of HCV genotype 1 infection in November and appears to offer a significantly improved tolerability profile over 
the existing protease inhibitors boceprevir and telaprevir.


Patient Profile
Current Concepts on the Patient with HCV and Cryoglobulinemia

Sandeep T. Samuel, MD; Andrew H. Talal, MD, MPH; Anthony D. Martinez, MD
Among HCV-infected patients, 75% develop chronicity, which can lead to cirrhosis and hepatocellular carcinoma. The binding and replication of HCV in extra-hepatic sites, particularly lymphoid tissues and subsequent immune system modulation, is fundamental to the extra-hepatic manifestations of HCV infection such as mixed cryoglobulinemia, porphyria cutanea tarda, sicca syndrome, lichen planus and idiopathic thrombocytopenic purpura. 


The Take Home
The Take Home: CROI 2014
Meeting highlights and analysis from the Conference on Retroviruses and Opportunistic Infections.

Trend Watch
Sleep Disturbances Common for Patients with HCV

Chronic fatigue associated with hepatitis C virus is associated with poor sleep quality and increased nocturnal activity, leading researchers to suggest that there may be an alteration of sleep architecture behind fatigue in HCV-associated encephalopathy.


2.7 Million US Residents Have Chronic HCV Infection

Investigators for a new study estimated that approximately 2.7 million US residents have chronic hepatitis C virus, which is about 500,000 fewer than in a similar analysis between 1999 and 2002.


Researchers Identify HCV Surface Protein, Raise Hope for Vaccine

Scientists at Rutgers University and Emory University have identified the structure of a hepatitis C virus surface protein, a finding that could potentially further the development of a vaccine.


Liver Disease Persists in HIV/HCV Coinfection Despite Antiretroviral Therapy

Patients coinfected with HIV and hepatitis C virus have higher rates of liver compensation compared with patients with hepatitis C virus monoinfection, despite the use of antiretroviral therapy, according to recent study results.
 

Vantage Point 
Antiviral Therapy for HCV in Liver Transplant Candidates
Steven A. Gonzalez, MD, MS
The emergence of direct-acting antiviral therapy has transformed the management of chronic hepatitis C virus infection. The availability of telaprevir and boceprevir in 2012, followed recently by simeprevir (Olysio, Janssen Therapeutics) and sofosbuvir (Sovaldi, Gilead), has provided clinicians with more highly effective and well-tolerated treatment options. An important subgroup of patients who have historically experienced the greatest challenges in HCV therapy are those with cirrhosis awaiting liver transplantation. Although these individuals may have the most to gain by achieving viral eradication, they have also been faced with lower efficacy, poor tolerance and safety concerns while undergoing therapy.

Monday, March 31, 2014

Advances in the Treatment of Hepatitis C

Advances in the Treatment of Hepatitis C as seen at CROI 2014

March 28, 2014
By Mariel Selbovitz
Source

The opening day of the 21st Conference on Rtroviruses and Opportuistic Infections (CROI 2014) featured a press conference on advances in the treatment of hepatitis C, with a focus on how new drugs may be used in the real world, given barriers such as high cost and a shortage of experienced medical providers.

As new Hepatitis C drugs are approved, more clinical trial options become available and interferon-free regimens near FDA approval, Hepatitis C treatment is changing rapidly. Several presentations at CROI 2014 focused on what has become the ever-evolving face of Hepatitis C treatment.

Anita Kohli presented data from the first three arms of the eight arm SYNERGY study1. The objective of the SYNERGY study is to use multiple drugs to target various stages of the HCV life cycle with the goal of shortening the duration of therapy.

Twenty treatment-naive patients were enrolled in each of the study arms for a total of 60 study participants. Four different drugs were used (2 as a co-formulated fixed dose tablet) to target different stages of the Hepatitis C life cycle.

Sofosbuvir is a nucleotide NS5B polymerase inhibitor and Ledipasvir is an NS5A inhibitor, both of which were used in all three arms as a fixed dose tablet. In the first arm, this regimen was given for 12 weeks. In the second arm, GS-9669, a non-nucleoside NS5B polymerase inhibitor (which works at a different site in the NS5B region than Sofosbuvir), was added. The third arm consisted of Sofosbuvir/Ledipasvir and GS-9451. GS-9451 is a protease NS3/4 inhibitor.

The study population reflected what researchers felt was an accurate representation of the HCV patient population in the U.S. and was a difficult to treat cohort. Across the three arms of the trial the average age of participants were 54- 57; 65- 80% were male, 80-95% were black, 55- 85% had Genotype 1a and 15-45% had genotype 1b. 75-90% maintained an unfavorable Il-28B genotype of CC or TT, 65- 75% had a viral load of greater than 800, 000 IU/mL and 25-40% had stage 3 or 4 liver disease.

Study results showed that 59 of the 60 patients across all 3 arms achieved SVR 12, and that 39 of the 40 patients in the two 6 week arms achieved SVR 12 after 6 weeks of therapy.

In the Sofosbuvir/Ledipasvir group all patients were virally suppressed below the level of quantification by week 4 and remained suppressed at SVR12. In the Sofosbuvir/Ledipasvir and GS-9669 group all patients were virally suppressed by week 4 and remained suppressed at end of treatment. One African American male with stage 3 liver disease, a high viral load and genotype 1a relapsed at week 4. All other patients achieved SVR12 in this arm. In the Sofosbuvir/Ledipasvir and GS-9451 arm, all patients were virally suppressed at week 4 and remained suppressed at SVR12.

Blood draws were taken over the initial 36 hours following the first medication dose on a subset of patients (n=29). Viral kinetic analysis was performed to determine if the addition of a third agent could enhance viral clearance of HCV and to develop a future model of treatment with combination regimens that could possibly shorten therapy even further.

Researchers found the 3 drug regimen of Sofosbuvir/Ledipasvir and GS-9451 led to a significantly faster decline of virus than the other 2 regimens, at day 7, day 14 and day 21.

Rapid normalization was seen of ALT and AST across all arms with 90-100% normalization by day 14.

No deaths or discontinuations occurred. All regimens were well tolerated. The highest percentages of adverse events were headache, which was seen in 25% of the Sofosbuvir/Ledipasvir group and 25% of the Sofosbuvir/Ledipasvir and GS-9669 group, and diarrhea at 5% in the Sofosbuvir/Ledipasvir group, 25% in the Sofosbuvir/Ledipasvir and GS-9669 group and 15% in the Sofosbuvir/Ledipasvir and GS-9451 group. Two grade 3 adverse events occurred but were not related to study drugs. One was site pain from a liver biopsy and the second was vertigo in a patient with a history of severe vertigo reported at baseline.

There were 11 grade 3 laboratory abnormalities in 9 patients:
In the Sofosbuvir/Ledipasvir arm there was one case each of elevated ALT, elevated AST, elevated LDL, hyperglycemia and hypoglycemia
In the Sofosbuvir/Ledipasvir and GS-9669 arm, 2 patients experienced a-symptomatic Hypophosphatemia
In the Sofosbuvir/Ledipasvir and GS-9451 one patient who had a history of anemia experienced decreased hemoglobin and three patients experienced elevated serum creatine but 2 had been elevated at baseline and the third developed renal insufficience after initiating 1600 mg/daily ibuprofen; all three returned to normal.

While most clinical trials of next-generation hepatitis C drugs are sponsored by pharmaceutical companies, the National Institutes of Allergy and Infectious Diseases (NIAID) is conducting parallel studies in underserved populations, looking for simple, well-tolerated treatments for people prone to difficulties with poor adherence and side effects. In the NIAID SYNERGY study, Anita Kohlifrom the National Institutes of Health and colleagues evaluated brief interferon- and ribavirin-free oral DAA regimens using a fixed-dose coformulation of Gilead Science’s recently approved HCV polymerase inhibitor sofosbuvir (Sovaldi, formerly GS-7977) and NS5A inhibitor ledipasvir (formerly GS-5885).

The SYNERGY studied found overall that 6 weeks of treatment with 3 Hepatitis C drugs that targeted different steps of the Hepatitis C viral life cycle was safe and efficacious, had a very high rate of viral clearance and offered a shorter course of treatment with fewer side effects then the currently available treatment.

Several new drugs and drug combinations are proving to be safe and efficacious for use in HCV patients. Trevor Hawkins of Southwest CARE Center in Sante Fe, New Mexico presented data on all-oral combination Daclatasvir, Asunaprevir and BMS-791325 for the treatment of HCV Genotype 12.

Daclatasvir (DCV) is a once- daily NS5A replication complex inhibitor that has been studied in over 5,500 patients and has been found to have a potent pan-genotypic activity in vitro. Asunaprevir (ASV) is a twice-daily, NS3 protease inhibitor that has been studied in over 2,000 patients and is active against genotypes 1,4,5, and 6 in vitro. BMS-791325 is a twice-daily, non-nucleoside NS5B polymerase inhibitor that is active against genotypes 1,3,4,5 and 6 in vitro. Various dose and drug-to-drug interactions have been seen with all three drugs.

A1443-014 is a randomized, phase IIb, 2 arm, 166 patient, open label study where patients received study drug for 12 weeks with follow-up to SVR 48. Patients were stratified by genotype 1a or 1b and whether or not they had biopsy-confirmed cirrhosis, receiving either DCV 30 mg BID +ASV 200 mg BID + BMS-791325 75 mg BID or DCV 30 mg BID+ ASV 200 mg BID+ BMS-791325 150 mg BID.

Researchers felt the study participant demographics were common for HCV clinical trials with an average 67% of the two arms being male; average age was 54, 83% were white and 16% African American. 82% had genotype 1a and 18% had genotype 1b and 38% had either FIB-3 or FIB-4 as determined by FibroSure/FibroTest. Those with FIB-4 received biopsies and an average 9% of the two arms had cirrhosis. Two/thirds were non-CC.

Study results found 92% of study participants achieved SVR. All treatment failures occurred in Genotype 1a. There were no predictors of failure other than Genotype.

In the DCV+ASV+BMS-791325 75 mg arm, 71/77 achieved SVR-12. The most frequent adverse events in this group were headache at 21.3%, diarrhea at 15%, fatigue at 15% and nausea at 12.5%. Grade 3/4 lab abnormalities included high AST in 1 patient and high glucose fasting serum in 1 patient.

In the DCV+ASV+ BMS-791325 150mg., 77/84 patients achieved SVR-12. In this arm the most frequent adverse events were headache in 27.9%, diarrhea in 15.1% and fatigue and nausea in 8.7% each. Grade 3/4 lab abnormalities included high glucose fasting serum in 1 patient and high bilirubin in 1 patient. There was 1 discontinuation due to adverse events and one patient discontinued BMS-791325 only and added peg/IFNa/RBV for 12 weeks.

Both regimens were found to be safe and effective and researchers recommend the continuation of clinical trials into Phase III trials.

Vincent LoRe from the University of Pennsylvania reported on a multi-site Veterans Administration (VA) study3, which analyzed predicting risk of end-stage liver disease (ESLD) in HIV/HCV co-infected patients for individualized HCV therapy decisions. The study evaluated the efficacy of utilizing laboratory and clinical variables to predict end-stage liver disease in HIV/HCV patients.

Researchers utilized data from the Veterans Aging Cohort Study (VACS) to identify 4,280 co-infected patients in the VA, all of who had been on HIV antiretroviral therapy for at least one year. Data was gathered of baseline predictors that included diabetes, Hepatitis B, race, obesity, a viral load greater than 400 c/mL, CD4 count below 200 cells/mm3 and a class 4 Fibrosis rating, from the initial year on therapy.

Study participants were followed for a total of 6.8 years where researchers found 8% of patients had developed ESLD as defined by hepatic liver decomposition, hepatocellular carcinoma or liver-related death.

Researchers discovered that utilizing Fibrosis 4 rating may be an effective means of means of predicting ESLD over time and could help to inform HCV treatment decisions. Additional predictors that were measured with FIB-4 were insufficient in adding greater predictability. Ongoing analysis continues for additional predictors.

REFERENCES
Combination Oral, Hepatitis C Antiviral Therapy for 6 or 12 Weeks: Results from the SYNERGY Trial A Kohil et al. Conference on Retroviruses and Opportunistic Infection, Boston, MA , March 3-6, 2014
(http://www.croiwebcasts.org/console/player/22048?mediaType=slideVideo&)
All-Oral Combination of Daclatasvir, Asunaprevir, and BMS-791325 for HCV Genotype 1 Infection GT Everson et al. Conference on Retroviruses and Opportunistic Infection, Boston, MA , March 3-6, 2014
(http://www.croiwebcasts.org/console/player/22046?mediaType=slideVideo&)
Predicting Risk of ESLD in HIV/HCV Patients for Individualized HCV Therapy Decisions V Lo Re et al. Conference on Retroviruses and Opportunistic Infection, Boston, MA , March 3-6, 2014
(http://www.croiwebcasts.org/console/player/22196?mediaType=slideVideo&)

Friday, March 7, 2014

Dr. Douglas Dieterich: REAL-WORLD HEPATITIS C TREATMENT

REAL-WORLD HEPATITIS C TREATMENT

The opening day of the 21st Conference on Rtroviruses and Opportuistic Infections (CROI 2014) featured a press conference on advances in the treatment of hepatitis C, with a focus on how new drugs may be used in the real world, given barriers such as high cost and a shortage of experienced medical providers....

Published March 6 2019 - By HIVandHepatitis

 


http://www.hivandhepatitis.com/hepati...

Chaired by Jean-Michel Pawlotsky, Hôpital Henri Mondor Créteil, France
Trevor Hawkins, Southwest CARE Center, Santa Fe, NM, US
Douglas Dieterich, Icahn School of Medicine at Mount Sinai, New York, NY, US
Anita Kohli, National Institutes of Health, Bethesda, MD, US
Marion G. Peters, University of California San Francisco, San Francisco, CA, US

Thursday, March 6, 2014

Shorter Treatment Strategy Beats Hepatitis C

Meeting Coverage
Shorter Treatment Strategy Beats Hepatitis C
Published: Mar 6, 2014
By Ed Susman , Contributing Writer, MedPage Today

BOSTON -- A 6-week treatment regimen appeared to be as effective as the more standard 12 weeks of therapy for patients with hepatitis C virus infection, researchers reported here at the annual Conference on Retroviruses and Opportunistic Infections.

In a pilot study that treated 20 patients in each of three arms, all patients treated with the combination of sofosbuvir (Sovaldi, nucleotide NS5B inhibitor) 400 mg with ledipasvir (NS5A inhibitor) 90 mg once daily for 12 weeks achieved a sustained virologic response at 12 weeks' post-treatment (SVR12), reported Anita Kohli, MD, an infectious disease fellow at the National Institutes of Health Clinical Center in Bethesda, Md.

But she also noted that two regimens using the same backbone and adding either the investigative agent GS-9669 (non-nucleoside NS5B inhibitor) 500 mg once daily or GS-9451 (a protease/NS3/4 inhibitor) 80 mg once daily for 6 weeks had similar outcomes: 95% of patients on GS-9669 achieving an SVR12, and 100% of patients on GS-9451 achieving an SVR12.

The one patient in the study who failed to achieve an SVR12 relapsed before SVR4; that individual had stage 3 liver disease, a high viral load, and unfavorable genotype, Kohli said.

All patients in all 3 arms were naive to treatment for hepatitis C virus. All patients were included in the 12-week arm, but patients diagnosed with cirrhosis were excluded from the 6-week trials.

"These results are not statistically significantly different from each other," Kohli told MedPage Today at a press briefing sponsored by the conference organizers.

"We find these results very promising. This was a pilot study," Kohli said. "We will follow these patients out to 48 weeks to see if the results are maintained."

A cure in the context of HCV is a sustained virologic response -- defined as undetectable viral RNA at some prespecified point after ending therapy, usually 12 or 24 weeks.

"What we have learned from this trial is that we can treat patients for shorter durations of therapy and we see that 6 weeks is effective," Kohli said.

"Secondly, these regimens are very simple -- 1, 2, or 3 pills a day. Third, our patient population is one that is historically very difficult to treat -- more than 80% of the patients were African American, most had genotype 1a, most had high viral loads, 25% to 30% of the patients had advanced-stage liver disease.

"The reason we wanted to look at the short-duration therapies is because we think it is very important in treatment of hepatitis C globally in limited resource settings. We really need very simple treatments for the 150 million to 180 million people globally," she said.

All the treatment regimens avoided the use of interferon, once the mainstay of treatment of hepatitis C virus, but a therapy that is difficult to tolerate for many patients. The use of interferon-free directly acting antiviral agents is an emerging approach to improve the efficacy and tolerability of therapy for hepatitis C virus, Kohli said.

However, she noted that the efficacy of interferon and ribavirin-free regimens shorter than 8 to 12 weeks has not been reported. One study evaluating sofosbuvir, ledipasvir, and ribavirin for 6 weeks showed an SVR12 rate of only 68%, she said. She also noted that the optimal combination of directly acting antiviral agents not been established.

Press conference moderator Jean-Michel Pawlotsky, MD, PhD, professor of medicine at Hopital Henri Mondor Creteil/University of Paris-Est, told MedPage Today that, while the results of the SYNERGY trial look interesting, they are not ready for routine implementation.

"There are very small numbers in this study," he said. "We have to see how this will apply to real-life patients. The danger is always to undertreat patients. If the time is too short and it works in a trial and you start treating real-life patients you can have failures. So we really need to extend this trial. It is interesting because it shows that some people can be cured in a very short duration of treatment."

Pawlotsky said he would not be comfortable treating his patients in this manner without more extensive studies.

Ledipasvir is not currently approved in the U.S. Its manufacturer, Gilead, filed last month for FDA approval of the drug in a fixed-dose combination with sofosbuvir.

The study was funded by the National Institutes of Health.

Kohli disclosed no relevant relationships with industry.

Pawlotsky disclosed no relevant relationships with industry.

Faldaprevir- Boehringer Ingelheim Announces Phase 3 SVR12 Results in HCV/HIV Co-Infected Patients

Boehringer Ingelheim Announces Phase 3 SVR12 Results in HCV/HIV Co-Infected Patients Treated with Faldaprevir

Additional drug-drug interaction data for faldaprevir combined with commonly prescribed HIV medications also presented at CROI 2014

Faldaprevir NDA has been accepted for review by U.S. FDA as part of a combination regimen for patients with chronic hepatitis C

For media outside of the US, the UK & Canada only

Ingelheim, Germany and Ridgefield, CT, March 6, 2014 – Today Boehringer Ingelheim announced results from STARTVerso®4 in patients with HCV/HIV co-infection. Hepatitis C viral cure 12 weeks after the conclusion of treatment (SVR12) was achieved by 72% of all patients in the trial. Patients were enrolled in either 120mg or 240mg faldaprevir dose groups. Further, 80% of all patients were eligible for randomization to a shortened duration of treatment (24 versus 48 weeks) because they achieved protocol-defined early treatment success (ETS)* and 86% of these patients achieved SVR12. STARTVerso®4 is a Phase 3 trial that enrolled 308 hepatitis C (HCV) treatment-naïve or experienced patients with HCV/HIV co-infection and evaluated the efficacy and safety of the investigational compound faldaprevir in combination with pegylated interferon and ribavirin (PegIFN/RBV).

"The SVR12 data from STARTVerso®4 are encouraging, especially given the inclusion of patients with cirrhosis," said Peter Piliero, MD, vice president, Clinical Development and Medical Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. "Comprehensive data from our STARTVerso® clinical trial program, including data from patients with HCV/HIV co-infection, have been filed with the FDA as part of our New Drug Application for faldaprevir."

In each faldaprevir dose group, 71% (120mg) and 72% (240mg) of patients achieved SVR12. SVR12 results were consistent across patients regardless of HCV genotype-1 subtype (GT1a or GT1b), presence of compensated cirrhosis, dose and duration of faldaprevir, and duration of PegIFN/RBV. In a post hoc analysis, 75% of patients with the Q80K variant achieved SVR12 compared with 71% of patients who did not have the variant.

Serious adverse events (AEs) were reported in 32 patients (10%). To date, 24 patients have prematurely discontinued faldaprevir due to AEs. The most frequent AEs in STARTVerso®4 were nausea (37%), fatigue (34%), diarrhea (27%), headache (25%) and weakness (23%). Patients will be followed to 24 weeks after the conclusion of treatment (SVR24).

In separate poster presentations at CROI, investigators described the results from analyses that evaluated drug-drug interactions of faldaprevir with common HIV medications, including: efavirenz, atazanavir/ritonavir, darunavir/ritonavir, raltegravir and tenofovir. In each of these analyses, there was no clinically relevant effect of faldaprevir on the pharmacokinetics of any of the HIV medications studied. Patients in STARTVerso®4 already taking ritonavir-boosted HIV protease inhibitors (darunavir or atazanavir) or efavirenz were enrolled into the 120mg and 240mg faldaprevir groups, respectively.

Boehringer Ingelheim HCV Development Update
The New Drug Application (NDA) for faldaprevir has been accepted for filing by the U.S. Food and Drug Administration (FDA). Faldaprevir is currently under review as a component of a combination antiviral treatment regimen for the treatment of chronic HCV infection in adult patients who are treatment-naïve or have been previously treated with interferon-based treatment, as well as those with compensated liver disease, cirrhosis, or HCV/HIV co-infection. The FDA target action date for faldaprevir is in the fourth quarter of 2014.

The NDA submission for faldaprevir is supported by Boehringer Ingelheim’s STARTVerso® (NCT01343888, NCT01297270, NCT01358864, NCT01399619) clinical trial program, a multi-study Phase 3 trial program that evaluated faldaprevir for 12 or 24 weeks in combination with pegylated interferon and ribavirin (PegIFN/RBV). The four trials that make up this program studied treatment-naïve, treatment-experienced, and HCV/HIV co-infected patients with chronic genotype-1 (GT1) HCV. The primary efficacy endpoint of each STARTVerso® trial is viral cure 12 weeks after the conclusion of treatment (SVR12).

In November 2013, Boehringer Ingelheim announced that the faldaprevir application for marketing authorization is under review by the European Medicines Agency (EMA). If authorized by the European Commission, faldaprevir could be available for marketing in the EU in the second half of 2014.

Following an assessment of the blinded Phase 3 trial data from HCVerso® 1 and 2 for the combination of deleobuvir, faldaprevir and ribavirin, Boehringer Ingelheim has decided to halt further development of deleobuvir-containing HCV regimens. Ongoing regulatory reviews of faldaprevir are not affected by the decision on the deleobuvir-containing regimens.

About Faldaprevir
Faldaprevir is an investigational, oral protease inhibitor that is specifically designed to target viral replication in the liver. Faldaprevir is an investigational compound that has not been approved by the FDA; its safety and efficacy have not been established.

Source

Tuesday, March 4, 2014

Daclatasvir/asunaprevir/BMS-791325: All-Oral HCV Regimen Works in 9 Out of 10

Related
Bristol-Myers' Hepatitis C combo Daclatasvir and Asunaprevir gets breakthrough designation
All-Oral HCV Regimen Works in 9 Out of 10

Published: Mar 4, 2014
By Ed Susman , Contributing Writer, MedPage Today

BOSTON -- An all-oral, 12-week regimen appears to successfully treat hepatitis C virus (HCV) infection in about 90% of patients, researchers reported here.

Of the 166 treatment-naive patients in the study, 92% achieved a sustained virologic response at 12 weeks (SVR-12) on the combination of the investigative NS5A inhibitor daclatasvir, the protease inhibitor asunaprevir and the non-nucleoside BMS-791325, said Trevor Hawkins, MD, chief medical officer at Southwest CARE Center and professor of medicine at the University of New Mexico in Santa Fe.

"The observed analysis showed a 92% SVR12, and in the modified intent-to-treat analysis -- wherein data at week 12 is counted as failure if it is missing -- [it] was 89%," Hawkins told MedPage Today at the annual Conference on Retroviruses and Opportunistic Infections.

A cure in the context of HCV is a sustained virologic response (SVR) -- defined as undetectable viral RNA at some prespecified point after ending therapy, usually 12 or 24 weeks.

At the end of treatment in Hawkins' study, 97.5% of those in the low-dose BMS-971325 group showed a complete viral response compared with 94.2% of those taking the high dose; the SVR4 was 92.4% in the low-dose group and 91.7% in the high-dose-treated patients. The SVR12 was achieved by 92.2% in the low-dose treatment group and by 91.7% of those taking high-dose BMS-791325, the researchers reported.

In the trial, Hawkins said that 9% of the patients were diagnosed with cirrhosis. He said that there did not appear to be a difference in outcome among the cirrhotic patients compared with those who were not cirrhotic -- 13 of the 15 cirrhotic patients achieved an SVR12.

Hawkins said that the next trials -- called UNITY 1 and UNITY 2 -- will separate cirrhotic and noncirrhotic patients to examine if there are differences in outcomes depending on the extent of liver disease. These trials will use the 75-mg dose of BMS-791325.

The trial he reported here showed that patients were able to tolerate the regimen. "There were two discontinuations due to adverse events in the entire 166-patient cohort," he said at a press conference.

The patients diagnosed with HCV genotype 1 were randomly assigned to receive a twice-daily regimen of daclatasvir 30 mg, asunaprevir 200 mg and BMS-791325 at 75 mg or 150 mg for 12 weeks. Hawkins said outcomes were similar for the 80 patients on BMS-791325 given 75 mg twice daily and the 86 patients given BMS-791325 at a dose of 150 mg twice daily.

"There were 11 virologic failures and we attempted to find out if there were any predictors of failure," he said. "The only thing that appeared to predict failure was being of genotype 1a. We tried to determine if there were any polymorphisms at baseline that would predict virologic failure, but we were unable to do that. There really was no obvious correlation."

In pilot studies, the 24-week SVR was 94% and the 12-week SVR was 94% with use of the 75-mg dose of BMS-791325; with the 150-mg dose, the 24-week SVR was 94% and the 12- week SVR was 89%.

The patients were about 54 years old, 67% were men, 83% were white, 82% were genotype 1a, and 15 patients in the study -- 9% -- were diagnosed with cirrhosis.

"This looks good," press conference moderator Jean-Michel Pawlotsky, MD, of the Hôpital Henri Mondor Creteil/University of Paris-Est, told MedPage Today. "There are several potential combinations that are going to work in patients with HCV. This combination with three drugs has good potency and a high barrier to resistance. This is promising."

The study was sponsored by Bristol-Myers Squibb.

Hawkins disclosed commercial interests with Gilead, Janssen, AbbVie, Bristol-Myers Squibb, BMS, Vertex, GlaxoSmithKline, Sangamo, Salix, Merck and ViiV. Co-authors include Bristol-Myers Squibb employees.

Pawlotsky had no disclosures.

Hepatitis C - New Interferon-Free Drugs for Hep C Show High Cure Rates

Related -
Hepatitis C- AbbVie to Present Late-breaker PEARL-III Study at the 21st Conference on Retroviruses and Opportunistic Infections

Medscape Medical News > Conference News

New Interferon-Free Drugs for Hep C Show High Cure Rates

Marcia Frellick
March 04, 2014

 BOSTON — A revolution is happening in the treatment of hepatitis C virus, with new interferon-free drugs bringing cure rates of more than 90%.

Results from several trials were presented on opening day here at the 2014 Conference on Retroviruses and Opportunistic Infections.

PEARL-III

In the PEARL-III trial, treatment-naïve noncirrhotic adults with chronic genotype 1b (GT1b) hepatitis C were treated with an investigational all-oral interferon-free treatment from AbbVie plus ribavirin. After 12 weeks of treatment, sustained virologic response rates reached 99.5%. Even in difficult-to-treat cirrhotic patients, response rates reached 92% to 96%.

"Therapies currently being developed for the treatment of hepatitis C offer patients new options with shorter durations of treatment," said Javier Boix, a spokesperson for AbbVie.

This investigational regimen is appropriate for broad use in all genotype 1 patient populations, and in subgroups with GT1a or GT1b disease, in both treatment-naïve and treatment-experienced patients, Boix told Medscape Medical News. It's also appropriate for "those who typically do not respond well to treatment, such as previous nonresponders to interferon-based therapy and patients with advanced liver fibrosis or cirrhosis," he added.

SYNERGY

This National Institutes of Health (NIH) SYNERGY study looked at 3 different regimens of interferon-free therapy in a difficult-to-treat hepatitis C patient population, 88% of whom were black. After 6 and 12 weeks of treatment, sustained virologic response rates reached 95% to 100%.

"One of the things we learned from this trial is that we can treat people with short durations of therapy," said Anita Kohli, MD, from the NIH in Bethesda, Maryland. "Also, these regimens are very simple. They are 1, 2, or 3 pills once a day," she explained.

PHOTON-1

The phase 3 PHOTON-1 study is the first study of an interferon-free agent in the treatment of patients coinfected with HIV and hepatitis C. After 24 weeks of the once-a-day nucleotide analog polymerase inhibitor sofosbuvir ( Sovaldi), from Gilead, overall sustained virologic response was 76% in patients with genotype 1 hepatitis C, 88% in those with genotype 2 disease, and 90% in those with genotype 3 disease.

In December 2013, the US Food and Drug Administration approved sofosbuvir for the treatment of chronic hepatitis C infection.

Reaching Those in Need

The development of hepatitis C drugs "in the past few years is unprecedented," said Lynn Taylor, MD, from the division of infectious diseases at Miriam Hospital, Brown Medical School, in Providence, Rhode Island.

In the United States, the next step is to build the infrastructure to get the new drugs to the people who need them, she told Medscape Medical News. This will include building up a workforce of people who treat hepatitis C and providing financial incentives and reimbursement reforms.

"Medicare and Medicaid are going to have to pick up the tab for these drugs," because hepatitis C most often occurs in low-income populations. "It's going to be a crisis," she said. "But it will also force people into a rational, deliberate, thoughtful discussion about what we are going to do about hepatitis C."

2014 Conference on Retroviruses and Opportunistic Infections (CROI). Presented March 3, 2014.

Monday, March 3, 2014

Hepatitis C- AbbVie to Present Late-breaker PEARL-III Study at the 21st Conference on Retroviruses and Opportunistic Infections

AbbVie to Present Late-breaker PEARL-III Study in Patients with Chronic Hepatitis C at the 21st Conference on Retroviruses and Opportunistic Infections

-- SVR(12) rates of 99 percent with and without ribavirin were achieved in genotype 1b patients new to treatment

-- Response rates in PEARL-III were also high in specific patient characteristics, such as gender, race and genetics

Mar 3, 2014
BOSTON, March 3, 2014 /PRNewswire/ -- The first detailed results from AbbVie's (NYSE: ABBV) pivotal phase III study, PEARL-III, were presented today as part of the 21st Conference on Retroviruses and Opportunistic Infections (CROI) press conference and will also be presented as a late-breaker at the conference on March 4. PEARL-III evaluated the efficacy and safety of 12 weeks of treatment with AbbVie's investigational therapy with or without ribavirin (RBV) in non-cirrhotic, adult patients with chronic genotype 1b (GT1b) hepatitis C virus (HCV) infection who were new to treatment. 

The PEARL-III study met its primary and secondary endpoints. In the 419-patient study, sustained virologic response rates 12 weeks post-treatment (SVR12) of 99.5 and 99.0 percent were achieved with the AbbVie regimen with and without RBV, respectively. There were no study drug discontinuations due to adverse events.

"Results from PEARL-III are encouraging, as they demonstrate AbbVie's regimen can achieve high rates of SVR, with and without ribavirin across several patient characteristics in those with genotype 1b chronic hepatitis C infection," said Peter Ferenci, M.D., professor of Gastroenterology and Hepatology, Medical University of Vienna.

PEARL-III enrolled patients across different demographics and characteristics. Response rates in patients with certain characteristics (male gender, Black race and IL28B non-CC genotypes) were examined, as these patient populations have historically been associated with having a decreased response to treatment. High response rates were observed across all patients in the study, including those with these characteristics.

"We are excited about the strong PEARL-III results which demonstrate the AbbVie regimen achieved high SVR rates with no discontinuations due to adverse events in patients new to treatment with genotype 1b infection," said Scott Brun, M.D., vice president, pharmaceutical development, AbbVie. "Additionally, with these data, we continue to be on track to begin major regulatory submissions in the second quarter of 2014. AbbVie will continue to disclose additional detailed phase III study results at future scientific congresses and in publications."

About Study M13-961 (PEARL-III)
PEARL-III is a global, multi-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of 12 weeks of treatment with AbbVie's regimen with and without RBV in non-cirrhotic, GT1b HCV-infected, treatment-naive adult patients.

The study population consisted of 419 GT1b treatment-naive patients with no evidence of liver cirrhosis: 209 patients randomized to the regimen without RBV for 12 weeks, and 210 patients randomized to the regimen with RBV for 12 weeks. Following 12 weeks of treatment, 99.0 percent receiving the regimen without RBV (n=207/209) and 99.5 percent receiving the regimen with RBV (n=209/210) achieved SVR12. Patients in the treatment arm without RBV received placebo in substitution for RBV.

Patients with different demographics and characteristics were enrolled in the study, including gender, race (Black vs. non-Black), Hispanic/Latino ethnicity, age, geographic region, body mass index (BMI), liver fibrosis stage, IL28B genotype and viral load.
Across treatment arms in PEARL-III, there were no documented relapses within 12 weeks post-treatment. No on-treatment virologic failures occurred in the treatment arm without RBV and a single virologic failure occurred in the treatment arm with RBV. While all patients in the study completed therapy, two patients in the arm without RBV were lost to follow-up and therefore were considered treatment failures.

The most commonly reported adverse events (>10 percent for either arm) were headache, fatigue, pruritus, nausea and asthenia, with pruritus and nausea occurring at a statistically higher rate in the treatment arm with RBV compared to the arm without RBV. Anemia occurred more commonly among patients in the RBV-containing arm with clinically significant anemia requiring RBV dose reductions occurring in 9 percent of these patients.

Additional information about AbbVie's phase III studies can be found on www.clinicaltrials.gov.

About AbbVie's Investigational HCV Regimen
 The AbbVie investigational regimen consists of the fixed-dose combination of ABT-450/ritonavir (150/100mg) co-formulated with ABT-267 (25mg), dosed once daily, and ABT-333 (250mg) with or without RBV (weight-based), dosed twice daily. The combination of three different mechanisms of action interrupts the HCV replication process with the goal of optimizing SVR rates across different patient populations.

AbbVie's HCV Development Program
The AbbVie HCV clinical development program is intended to advance scientific knowledge and clinical care by investigating an interferon-free, all-oral regimen with and without RBV with the goal of producing high SVR rates in as many patients as possible, including those that typically do not respond well to treatment, such as previous non-responders to interferon-based therapy or patients with advanced liver fibrosis or cirrhosis.
ABT-450 was discovered during the ongoing collaboration between AbbVie and Enanta Pharmaceuticals (NASDAQ: ENTA) for HCV protease inhibitors and regimens that include protease inhibitors. ABT-450 is being developed by AbbVie for use in combination with AbbVie's other investigational medicines for the treatment of HCV.

Safety Information for Ribavirin and Ritonavir
Ribavirin and ritonavir are not approved for the investigational use discussed above, and no conclusions can or should be drawn regarding the safety or efficacy of these products for this use.
There are special safety considerations when prescribing these drugs in approved populations.
Ritonavir must not be used with certain medications due to significant drug-drug interactions and in patients with known hypersensitivity to ritonavir or any of its excipients.

Ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus and must not be used alone for this use. Ribavirin causes significant teratogenic effects and must not be used in women who are pregnant or breast-feeding and in men whose female partners are pregnant. Ribavirin must not be used in patients with a history of severe pre-existing cardiac disease, severe hepatic dysfunction or decompensated cirrhosis of the liver, autoimmune hepatitis, hemoglobinopathies, or in combination with peginterferon alfa-2a in HIV/HCV co-infected patients with cirrhosis and Child-Pugh score greater than or equal to 6.
See approved product labels for more information.

About AbbVie
AbbVie is a global, research-based biopharmaceutical company formed in 2013 following separation from Abbott Laboratories.  The company's mission is to use its expertise, dedicated people and unique approach to innovation to develop and market advanced therapies that address some of the world's most complex and serious diseases.  AbbVie employs approximately 25,000 people worldwide and markets medicines in more than 170 countries.  For further information on the company and its people, portfolio and commitments, please visit www.abbvie.com.  Follow @abbvie on Twitter or view careers on our Facebook or LinkedIn page.

Forward-Looking Statements
Some statements in this news release may be forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. The words "believe," "expect," "anticipate," "project" and similar expressions, among others, generally identify forward-looking statements. AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Such risks and uncertainties include, but are not limited to, challenges to intellectual property, competition from other products, difficulties inherent in the research and development process, adverse litigation or government action, and changes to laws and regulations applicable to our industry.

Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," in AbbVie's 2012 Annual Report on Form 10-K/A, which has been filed with the Securities and Exchange Commission. AbbVie undertakes no obligation to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law.

SOURCE AbbVie
For further information: Media: Elizabeth Hoff, +1 (847) 935-4236, elizabeth.hoff@abbvie.com, or Javier Boix, +1 (847) 937-6113, javier.boix@abbvie.com; Investor Relations: Elizabeth Shea, +1 (847) 935-2211, elizabeth.shea@abbvie.com