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EASL 2013, International Liver Conference, AbbVie

Apr 28, 2013 - 0 comments
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EASL 2013

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International Liver Conference

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ABT 450/r

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ABT 267

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ABT 333



AbbVie reported results of a trial involving a 12 week regimen of 3 drugs combined with RBV trials (90% SVR12):

New Data from AbbVie's Phase IIb Aviator Trial Demonstrate High Sustained Viral Response Rates Across Multiple Patient Types with HCV Genotype 1

- 96 percent of treatment-naive patients and 93 percent of prior null responders treated with AbbVie's investigational IFN-free, triple-DAA combination therapy achieve SVR24

- Additional analyses looks at response rates in patients with differing baseline factors including gender, viral load and fibrosis stage

Apr 23, 2013

AMSTERDAM, April 23, 2013 /PRNewswire/ -- (NYSE: ABBV)  – Results from "Aviator,"  AbbVie's phase IIb clinical trial of its investigational direct-acting antivirals (DAAs) for the treatment of hepatitis C virus (HCV) infection, continue to demonstrate high sustained viral response (SVR) rates against genotype 1 HCV, across patient types. Data show greater than 90 percent SVR were achieved in patients new to treatment and in patients who had previously failed treatment with pegylated interferon and ribavirin (null responders). In addition, similar high SVR rates observed after 12 and 24 weeks of treatment in the Phase IIb trial reinforce the adequacy of the 12-week treatment duration for the investigational interferon-free, triple DAA combination.  The triple-DAA combination is currently being studied in Phase III clinical trials. Results will be featured in the official press conference at the 2013 International Liver Congress® (ILC) in Amsterdam on Wednesday, April 24 at 11:00 CEST and presented on Thursday, April 25.

"These new results from the Aviator study further demonstrate that this investigational all-oral therapy combination can achieve high sustained viral response after 12 weeks of treatment," said Kris Kowdley, M.D., Director of the Liver Center of Excellence and Director of Research in the Digestive Disease Institute at Virginia Mason Medical, and Clinical Professor of Medicine at the University of Washington in Seattle. "The consistency of high sustained viral response rates that we have seen in clinical trials across populations is encouraging, especially given the proportion of patients with these characteristics who have failed with interferon plus ribavirin treatment."
"AbbVie's clinical development program aims to improve virologic cure rates, including in patients who have historically been harder to treat with current therapies, such as prior null responders. While further studies are required to confirm these findings, we remain encouraged by the high viral response rates and the safety profile we have seen in the Aviator study," said Barry Bernstein, divisional vice president, infectious disease development, AbbVie. "Our Phase III trials are progressing well and we remain focused on bringing an interferon-free treatment option to patients with HCV genotype 1 infection."

About Study M11-652 (Aviator)
The objective of this phase 2b study was to assess the safety, and efficacy of ABT-450/r (dosed 100/100 to 200/100mg once daily), ABT-267 (25mg once daily), ABT-333 (400mg twice daily) and ribavirin in non-cirrhotic treatment-naive patients and prior peg-interferon/ribavirin null responders administered for 8, 12 or 24 weeks. Enrollment was open to GT1-infected patients regardless of IL28B host genotype and ribavirin dosing was weight-based.

A summary of key data from the trial is below:
Treatment-Naive Null Responders
Duration 8 weeks 12 weeks 24 Weeks 12 weeks 24 weeks
Regimen ABT-450/r
ABT-267
ABT-333
RBV ABT-450/r

ABT-333
RBV ABT-450/r
ABT-267

RBV ABT-450/r
ABT-267
ABT-333
ABT-450/r
ABT-267
ABT-333
RBV ABT-450/r
ABT-267
ABT-333
RBV ABT-450/r
ABT-267

RBV ABT-450/r
ABT-267
ABT-333
RBV ABT-450/r
ABT-267
ABT-333
RBV
Number dosed 80 41 79 79 79 80 45 45 43
Breakthrough 0 1 1 1 0 0 0 3 1
Relapse 10 4 8 5 1 2 5 0 0
SVR12 (ITT) 89% 85% 91% 90% 99% 93% 89% 93% 98%
SVR24 (ITT) 88% 83% 89% 87% 96% 90% 89% 93% 95%
For the 12-week triple-DAA regimen with ribavirin being studied in Phase 3 trials:
• 99% of treatment-naive patients achieved SVR12, 96% achieved SVR24 in this intent-to-treat analysis
• 93% of prior null responders achieved SVR12 and SVR24
• The single relapse with this regimen occurred at post-treatment week two
With the triple-DAA plus ribavirin regimen, comparable SVR24 response rates were also seen in treatment naive patients and null responder patients across HCV subtype, IL28B genotype and baseline HCV-RNA levels and severity of fibrosis.  

SVR24 by patient subtype in the "Aviator" study

Characteristic Treatment Naive Null Responders
GT1a 91% (n=108) 93% (n=55)
GT1b 98% (n=50) 97% (n=33)
Non-CC  IL28B genotype 95% (n=115) 94% (n=85)
CC IL28B genotype 89% (n=44) 100% (n=3)
Viral Load (≥7 log) 89% (n=35) 91% (n=22)
Viral load (<7 log) 94% (n=124) 96% (n=66)
Fibrosis Stage (F0-F1)* 94% (n=113) 95% (n=41)
Fibrosis Stage (F2-F3)* 91% (n=42) 93% (n=45)
Male 92% (n=78) 93% (n=55)
Female 94% (n=81) 97% (n=33)

*The fibrosis analysis was post-hoc based on biopsy or non-invasive testing at screening.
The safety profile seen in this study is consistent with the initial presentation of results in November 2012. Of the 247 patients included in this analysis, four patients (1.6 percent) discontinued the study because of drug-related adverse events.  Serious adverse events were noted in 4 patients (1.6 percent), with one (arthralgia) considered possibly drug-related.  Other events reported in more than 10 percent of patients included headache, fatigue, nausea, insomnia, and diarrhea.  Grade 3-4 laboratory abnormalities in total bilirubin (six patients) and ALT (one patient) were noted; all resolved with continued dosing.

About Study M11-652 (Aviator)
The objective of this phase 2b study was to assess the safety, and efficacy of ABT-450/r (dosed 100/100 to 200/100mg once daily), ABT-267 (25mg once daily), ABT-333 (400mg twice daily) and ribavirin in non-cirrhotic treatment-naive patients and prior peg-interferon/ribavirin null responders administered for 8, 12 or 24 weeks. Enrollment was open to GT1-infected patients regardless of IL28B host genotype and ribavirin dosing was weight-based.

About the Hepatitis C Virus  
Across the world, about 160 million people are chronically infected with hepatitis C.1 Hepatitis C is an inflammation of the liver caused by an infection with the hepatitis C virus (HCV).2  HCV is transmitted when an infected person's blood enters the bloodstream of another person.3
For the hepatitis C virus, there are six major HCV genotypes (GT1-6).4 Presently, there is no vaccine for the hepatitis C virus (HCV) infection.3 Decision to treat is dependent on a number of factors such as the amount of liver damage present, other conditions the patient may have, amount of virus in the body, and viral genotype.4 If treatment is needed, a hepatitis C infection is typically treated with a combination of antivirals.3
About AbbVie's HCV Development Programs

AbbVie's HCV portfolio includes investigational medicines with three different mechanisms of action, including protease (ABT-450/r), polymerase (ABT-333) and NS5A (ABT-267) inhibitors, currently being studied in clinical trials. ABT-450 is being developed with low dose ritonavir which enhances the pharmacokinetic properties of ABT-450. The use of ritonavir 100mg with ABT-450 for the treatment of HCV is investigational.
ABT-450 was discovered during the course of a collaboration between AbbVie and Enanta Pharmaceuticals 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. AbbVie is well-positioned to explore combinations and co-formulations of these medicines.

Ritonavir Use in the Treatment of HIV
Ritonavir is in a class of medicines called the HIV protease inhibitors. Ritonavir is used in combination with other anti-HIV medicines to treat people with human immunodeficiency virus (HIV) infection. Ritonavir is for adults and for children greater than 1 month in age and older.
Ritonavir does not cure HIV infection or AIDS and does not reduce the risk of passing HIV to others. People taking ritonavir may still get opportunistic infections or other conditions that happen with HIV infection. Some of these conditions are pneumonia, herpes virus infections, and Mycobacterium avium complex (MAC) infections.

Ritonavir Safety in Treatment of HIV
Patients should not take ritonavir with certain medicines, as these can cause serious or life-threatening problems such as irregular heartbeat, breathing difficulties, or excessive sleepiness. Patients should not take ritonavir if they have had a serious allergic reaction to any of its ingredients. Some patients taking ritonavir may develop liver and pancreas problems, which can cause death.

Patients may develop large increases in triglycerides and cholesterol, diabetes, high blood sugar, changes in body fat, increased bleeding in people with hemophilia, allergic reactions, and/or changes in heart rhythm. Patients may develop signs and symptoms of infections that they already have after starting anti-HIV medicines.

http://abbvie.mediaroom.com/2013-04-23-New-Data-from-AbbVies-Phase-IIb-Aviator-Trial-Demonstrate-High-Sustained-Viral-Response-Rates-Across-Multiple-Patient-Types-with-HCV-Genotype-1

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Interferon-free, triple-DAA regimen safe, effective for chronic HCV
April 26, 2013

Nearly all patients with chronic hepatitis C treated with an interferon-free drug regimen for 12 or 24 weeks experienced sustained virologic response in a study presented at the International Liver Congress in Amsterdam.

Researchers administered 100-200 mg HCV protease inhibitor ABT-450 (AbbVie) with 100 mg ritonavir (ABT-450/r) once daily to patients with chronic hepatitis C genotype 1, along with 25 mg NS5A inhibitor ABT-267 once daily and 400 mg non-nucleoside NS5B inhibitor ABT-333 twice a day, and weight-based ribavirin, for 12 or 24 weeks. The cohort included 79 12-week and 80 24-week recipients among treatment-naive patients, and 45 12-week and 43 24-week recipients among previous nonresponders. Patients were either treatment-naive or nonresponsive to prior pegylated interferon/ribavirin therapy.

Sustained virologic response (SVR) rates at 4 weeks among treatment-naive participants were 98.7% in the 12-week and 96.2% in the 24-week group. Among prior nonresponders, SVR4 rates were 93.3% in the 12-week and 97.7% in the 24-week groups.

Among treatment-naive patients, SVR12 was 99% in the 12-week and 93% in the 24-week group, while nonresponders experienced SVR12 in 93% of 12-week and 98% of 24-week cases. SVR24 was achieved by 96% of 12-week and 90% of 24-week treatment-naive participants and 93% of 12-week and 95% of 24-week nonresponders. Across the cohort, SVR was similar regardless of IL28B genotype, baseline HCV RNA levels, fibrosis stage and infection with HCV genotype 1a compared with 1b.

Commonly reported events included headache, fatigue, insomnia, diarrhea and nausea. Four patients withdrew from the study after experiencing serious adverse events.

“The consistency of high sustained viral response rates that we have seen in clinical trials across populations is encouraging, especially given the proportion of patients with these characteristics who have failed with interferon plus ribavirin treatment,” researcher KrisV. Kowdley, MD, director of research at the Digestive Disease Institute at Virginia Mason Medical Center in Seattle, said in a press release.

Phase 3 trials are under way for the 12-week regimen.

http://hepatitiscnewdrugs.blogspot.com/2013/04/easl-interferon-free-triple-daa-regimen.html



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