ABT-450/r; ABT-267, and ABT-333 w-RBV-High SVR rates among chronic HCV patients

High SVR rates with DAA regimen among chronic HCV patients

July 5, 2013
Sustained virologic response to a regimen of three antivirals and ribavirin was highly prevalent with or without a ribavirin dose reduction among patients with chronic HCV in a study presented at the International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention in Kuala Lumpur, Malaysia.

Researchers evaluated 247 noncirrhotic patients with chronic HCV genotype 1, including 159 treatment-naive patients and 88 who were nonresponsive to previous interferon-based therapy. Patients were assigned 12 or 24 weeks of treatment with a combination of three direct-acting antivirals (DAA): HCV protease inhibitor ABT-450/r; NS5A inhibitor ABT-267, and non-nucleoside NS5B inhibitor ABT-333, along with weight-based ribavirin (RBV).

Full Story »

The State Of The Hepatitis C Pill Race: Gilead Vs. AbbVie

Investment commentary

The State Of The Hepatitis C Pill Race: Gilead Vs. AbbVie

 

Jun 20 2013

Peter Geschek

Gilead Sciencies (GILD) is believed to be leading the hepatitis C pill race, but AbbVie (ABBV) is not far behind. According to Scott Brun, AbbVie's head of pharmaceutical development, AbbVie may even win the race.

In June, at the Goldman Sachs Annual Global Healthcare Conference, he said:

"I'll say that it is a very tight race and like I said we're executing extremely well and I think we've got a very good shot at being first, but it's close."

Gilead

In a Phase II trial, Gilead's all-oral hepatitis C treatments sofosbuvir and ledipasvir, an NS5A inhibitor, cured 95 percent of patients after eight weeks of the therapy.

Sofosbuvir, which Gilead acquired in 2012 in the famous $11 billion acquisition of Pharmasset, has proved itself in four completed Phase III studies.

In May, following the encouraging interim results from a Phase II trial of sofosbuvir and ledipasvir, Gilead Sciences announced plans for a Phase III trial of a fixed dose of the two drugs. Called ION-3, the study will test a once-daily fixed-dose combination therapy of the two drugs both with and without ribavirin for eight weeks, as well as without ribavirin for 12 weeks. Six hundred non-cirrhotic, new-to-treatment patients with genotype 1 of the virus will participate in the trial.

In June, Gilead received a priority review designation from the FDA, a step that can save about four months in the approval process.

Confident in approval, Gilead is getting ready for the launch of sofosbuvir in the first quarter of 2014 in the U.S. and the second quarter in Europe by preparing sales teams and arranging training opportunities for physicians.

AbbVie

According to Brun, Gilead's advantage is overstated.

AbbVie is running 6 Phase III trials in 30 countries around the world with over 2200 patients.

It is running a dedicated study in cirrhotic patients, who are the hardest to treat of all. Cirrhosis means the liver is scarred, and it functions poorly. Cirrhosis is considered the final stage of chronic liver disease. AbbVie's treatment represents a possible cure, even for these hard-to-treat patients.

AbbVie's HCV portfolio includes experimental medicines with three different mechanisms of action. The compounds in the studies are ABT-450/r (protease inhibitor and ritonavir), ABT-267 (NS5A inhibitor) and ABT-333 (non-nucleoside polymerase inhibitor).

AbbVie's treatment will require three pills in the morning and one at night, according to Brun. In a Phase II trial with the drugs, 90 percent of patients who completed the eight-week regimen had the virus cleared from their body.

Some analysts consider AbbVie's treatment cumbersome compared to Gilead's because it requires four pills a day. But according to Brun, this is a very manageable regimen when you consider the situation of the HIV infected patients who receive Ritonavir (AbbVie's drug for HIV) boosted regimens for a lifetime on a much more complicated schedule. It is a matter of patient education.

AbbVie also is working on next generation programs already: ABT-493 is a protease inhibitor and ABT-530 is an NS5A inhibitor, both with very favorable pharmacologic characteristics, and neither will need Ritonavir boosting.

AbbVie also testing a regimen in Japan for genotype 1b patients requiring two pills once a day for 12 weeks with no Ribavirin. It is using the co-formulation of the ABT-450 and ABT-267 with Ritonavir. This combination is also being prepared for western markets.

Combos

Competitiors to Gilead and AbbVie, including Medivir (MVRBF.PK), Johnson & Johnson (JNJ), Bristol-Myers Squibb (BMY), Merck (MRK) and Vertex Pharmaceuticals (VRTX), among others, are all developing new oral hep C treatments.

The major challenge to development of an all-oral, interferon-free treatment is drug resistance.

Hep C circulates in the blood as a mixture of viruses with various sequences. It has been estimated that pre-existing drug resistance variants with one, two, three and even four mutations may be present in most hep C-infected patients and account for the rapid development of drug resistance on exposure to direct-acting antiviral drugs.

For a successful treatment it maybe necessary to use several direct-acting antiviral drugs in combination, and each of the components in a combination should have potent antiviral activity, possess non-overlapping resistance profile, and have limited or manageable drug interactions combined with minimal adverse effects.

There are a great number of combos tested in clinical trials.

Medivir has posted stellar interim data from its Phase 2a study of its hep C treatment simeprevir combined with Gilead's sofosbuvir. Medivir is a Swedish company working in partnership with Johnson & Johnson on this project. The combo therapy cleared the virus in 100 percent of genotype 1 patients.

Vertex's drug is also testing its experimental drug, VX-135 with Medivir's simeprevir.

While Gilead is unlikely to pursue a partnership with Medivir and J&J since the company is developing a combination of its own therapies, doctors may prescribe the pair off-label, provided the price is reasonable and payers are willing to pay for it.

Investors' summary

The hep C market is bigger than HIV.

Intravenous drug use, dirty tattoo parlors, tainted blood transfusions and carriers infecting offspring are some of the ways that millions of people around the world have contracted hepatitis C.

Hepatitis C attacks the liver and can lead to liver cancer. The virus affects about 150 million people worldwide and the market for new pills is estimated at $20 billion. Gilead's drug is projected to have annual sales of $6.03 billion by 2016, according to an average of 10 analysts estimates compiled by Bloomberg.

The introduction of pills will increase the overall market. Gilead estimates that 150,000 patients may seek treatment in the U.S. when these new drugs hit the market, which compares to the current 85,000 patients.

For both Gilead and AbbVie, a success in the hep C market is vitally important.

Gilead acquired Pharmasset in the 2011 buyout for about $11 billion, and at that time, some analysts believed that wager to be way too high. Now investors are anxious to see a return on it.

AbbVie currently is getting most of its earnings from its arthritis drug Humira, the world's best-selling drug, which is facing a patent expiry in several years, and a success with the hep C therapy would go a long way in strengthening its pipeline.

The prize each competitor in the race hopes to win is huge: a share of a $20 billion market. There is tremendous pent-up demand for oral therapies that can quickly wipe out hep C without using interferon.

At the Goldman Sachs conference, an analyst asked Abbvie if it is planning to challenge Gilead on the drug's price since Gilead has a much higher cost base as a result of having purchased Pharmasset for billions. The answer was that Abbvie does not price its products in this manner, and its pricing is based on estimating the value to the patients.

In the hep C race, "Gilead will be first, AbbVie will be on roughly the same timeline, Bristol-Myers will be somewhere after that," said Marshall Gordon, a New York-based analyst with Legg Mason Inc.'s ClearBridge Investments affiliate.

"To be fair, Gilead's drug looks better, but not that much better," Gordon said.

Source - Seeking Alpha

Source: The State Of The Hepatitis C Pill Race: Gilead Vs. AbbVie

http://seekingalpha.com/article/1513452-the-state-of-the-hepatitis-c-pill-race-gilead-vs-abbvie?source=feed

Related
Drew Armstrong @ Bloomberg  - Jun 13, 2013 : AbbVie Says It Can Be First With All-oral hepatitis C drugs

AbbVie's Investigational noninterferon HCV treatment effective across patient groups

Frederick A. Nunes, MD, Associate Professor of Medicine, Penn Medicine. Discussing his presentation at Digestive Disease Week 2013 in Orlando, Fla.: #514; Interferon‐free Regimens of ABT‐450/r, ABT‐267, ABT‐333, and Ribavirin Achieve High Sustained Virologic Response 4 Weeks Post‐Treatment (SVR4) Rates in Patients With Chronic HCV Genotype 1 Regardless of Race, Ethnicity, or Other Baseline characteristics.
Source - Healio

View Slides @ NATAP
DDW
Response to 3 DAAs + RBV by Patient Characteristics: INTERFERON-FREE REGIMENS OF ABT-450/r, ABT-267, ABT-333, AND RIBAVIRIN ACHIEVE HIGH SUSTAINED VIROLOGIC RESPONSE 12 WEEKS POST-TREATMENT (SVR12) RATES IN PATIENTS WITH CHRONIC HCV GENOTYPE 1 REGARDLESS OF RACE, ETHNICITY, OR OTHER BASELINE CHARACTERISTICS

May 6
AbbVie's Investigational Hepatitis C Virus Regimen Gets Breakthrough-Therapy Designation

May 24

Digestive Disease Week
Investigational noninterferon HCV treatment effective across patient groups

By: SHARON WORCESTER, Internal Medicine News Digital Network



Dr. Frederick Nunes

ORLANDO – Both 12- and 24-week regimens of an investigational interferon-free therapy for hepatitis C were associated with high sustained virological response rates at 12 weeks post treatment in a phase II study of patients with hepatitis C virus genotype 1 who had baseline characteristics associated with poor response to interferon-based therapies.

The findings of this subgroup analysis of the randomized, open-label, multicenter Aviator trial demonstrate that the high response rates recently reported for the entire cohort also apply to patients with older age, black race, Hispanic/Latino ethnicity, interleukin (IL)-28B non-cc genotype, and higher body mass index (BMI), Dr. Frederick Nunes reported at the annual Digestive Disease Week.

The Aviator trial assessed the safety and efficacy of various dosing regimens and combinations of three AbbVie investigational direct-acting antivirals (DAAs) with or without ribavirin, including the potent hepatitis C virus (HCV) protease inhibitor ABT-450 dosed with 100 mg of ritonavir (ABT-450/r, dosed at 100 or 150 mg daily), the NS5A inhibitor ABT-267 (25 mg daily), and the non-nucleoside NS5B inhibitor ABT-333 (400 mg twice daily). A total of 247 patients were included in the subanalysis, Dr. Nunes reported at the meeting.

The regimen that included all three investigational drugs and ribavirin, known as 3 DAA/RBV, was associated with sustained virological response rates of 99% and 93% at 12 weeks in treatment-naive patients and previous peg-interferon/ribavirin (peg-IFN/RBV) null responders, respectively, said Dr. Nunes, who is clinical associate professor of medicine in the University of Pennsylvania Health System, and section chief of gastroenterology at Pennsylvania Hospital, Philadelphia.

In the current analysis, high sustained virological response rates at 12 weeks (SVR12) were also achieved in the 247 patients with chronic HCV genotype 1, including 159 treatment-naive and 88 previous peg-IFN/RBV null responders, who were assigned to 12 or 24 weeks of 3 DAA/RBV. The virological response rates were 99% and 93% for the treatment-naive 12- and 24-week groups, respectively, and 93% and 98% for the null responder 12- and 24-week groups.

The high responses occurred regardless of treatment duration, age, race, ethnicity, BMI, Homeostatic Model of Assessment–Insulin Resistance (HOMA-IR), IL-28B host genotype, or baseline viral load. The rates did not differ significantly on any comparison made in treatment-naive patients or previous null responders, he said.

In the treatment-naive patients, no breakthroughs occurred, although 1% of those in the 12-week treatment arm relapsed, and 3% of the 24-week treatment group relapsed.

In the null responder group, no relapses occurred, but breakthroughs occurred in 7% of those in the 12-week treatment arm, and in 2% of the 24-week treatment arm, he said.

Treatment was safe and generally well tolerated. Four patients discontinued treatment due to drug-related adverse events, most commonly fatigue (in 32.7% and 23.9% of treatment-naive and null responders, respectively) and headache (31.4% and 30.7%, respectively).

One patient had a serious adverse event (arthralgia) considered to be possibly related to the study drug regimen.

Because ribavirin was included in the treatment regimens, it is impossible to tease out whether the adverse events were associated with that drug or with the investigational DAAs, Dr. Nunes noted.

Patients included in the study were noncirrhotic adults aged 18-70 years with a BMI between 18 and 38 kg/m², and HCV genotype 1.

 

"The overall efficacy was excellent irrespective of the baseline grouping. So black race, Hispanic/Latino ethnicity, age greater than 50, BMI over 30, male gender, HOMA-IR greater than 3, IL-28B non-cc genotype, and viral load greater than 7 logs all had very high SVR12 response rates," Dr. Nunes said.

 

The safety and efficacy of this interferon-free 3 DAA/RBV therapy will be further explored in phase III studies, he said.

 

Dr. Nunes has received grant or research support from Merck, Abbott Laboratories, and Roche Pharma AG.

 

http://www.internalmedicinenews.com/news/conference-news/digestive-disease-week/single-article-2013/investigational-noninterferon-hcv-treatment-effective-across-patient-groups/b3d9ead21f9bc4f7c32f92a1d2bfe0f3.html

EASL - Interferon-free, triple-DAA regimen safe, effective for chronic HCV

Healio › Hepatology › Chronic Hepatitis › News

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.

For more information:

Kowdley KV. #3: Safety and Efficacy of Interferon-Free Regimens of ABT-450/R, ABT-267, ABT333 ± Ribavirin in Patients With Chronic HCV GT1 Infection: Results From the Aviator Study. Presented at: The International Liver Congress 2013; April 24-28, Amsterdam

Meeting News Coverage

EASL: Direct-acting antivirals now ready for prime time with promising alternatives on the way

Direct-acting antivirals now ready for prime time with promising alternatives on the way

Studies show encouraging data in a wide range of HCV patient populations

Amsterdam, The Netherlands, Wednesday 24 April 2013: New data from a number of clinical trials presented for the first time at the International Liver Congress™ 2013 demonstrate encouraging results in the use of new direct-acting antiviral agents (DAAs) for the treatment of hepatitis C.

The following covers key results from the much anticipated Phase III trials conducted among HCV patients with a range of genotypes (GT 1 to 6) on DAA treatment.

POSITRON

A study of interferon (IFN)-ineligible, IFN-intolerant, or IFN-unwilling cirrhotic and non-cirrhotic GT 2 and 3 HCV-infected patients treated with a combination of sofosbuvir and ribavirin for 12 weeks achieved a high SVR12 rate without evidence of resistance.1 In the POSITRON Phase III trial, the SVR12 rate of 78% for sofosbuvir and ribavirin (161/207) was superior to placebo (0%, p< 0.001) and all 278 patients became HCV RNA negative on treatment. In terms of adverse events only 2% of patients discontinued treatment in the sofosbuvir + ribavirin group due to adverse events vs. 4% in the placebo group.

NEUTRINO

Treatment with a combination of sofosbuvir, peginterferon alfa-2a and ribavirin for 12 weeks achieved 90% SVR12 in treatment naïve genotype 1, 4, 5, or 6 HCV-infected patients with no viral resistance detected in failures, according to the results of the Phase III NEUTRINO study.2 The regimen was well tolerated and is a short, simple and effective treatment option for patients with these genotypes. A total of 327 patients (292 genotype 1, 28 genotype 4, 7 genotype 5/6) were enrolled and received the study drug.

EASL Secretary General Prof. Mark Thursz commented on the studies: “Unlike the US, in Europe and Asia genotype 3 is quite common. As such for European audiences the interferon-free results in genotype 3 are not as impressive as expected; however the side effect profile and lack of viral resistance means that longer treatment durations will be evaluated in the near future. In the meantime, we feel it’s not time to bury pegylated interferon just yet.”

“Many patients can tolerate 12 weeks of an interferon based regime particularly when it produces SVR rates of more than 90%; so clearly the results of the NEUTRINO study will be welcomed by clinicians and patients” added Prof. Thursz.

STARTVerso™1

Faldaprevir, an oral once-daily protease inhibitor, in combination with peginterferon alfa-2a and ribavirin (PegIFN/RBV) significantly increased SVR12 rates in treatment-naïve HCV GT-1 patients in Europe and Japan compared with PegIFN/RBV alone and was well tolerated.3 In total 652 patients were treated and 88% of patients treated with faldaprevir were eligible to stop all treatment at week 24.

QUEST-1 and -2

QUEST-1: Simeprevir, an oral once-daily protease inhibitor, in combination with peginterferon alfa-2a and ribavirin (PegIFN/RBV) achieved SVR12 rates of 80% compared to placebo, 50% (p<0.001).4 Of the 394 patients, 85% in the simeprevir treatment group were eligible to complete treatments at week 24. On-treatment failure rate was also much lower with simeprevir treatment, compared to placebo.
QUEST-2: Simeprevir versus placebo as part of regimen including PegIFN or PegIFN/RBV was well tolerated.5 SVR12 rates significantly increased in the simeprevir group compared to placebo (81 vs. 50% respectively (p<0.001) and of the 391 patients treated, 91% were eligible to stop all treatment at week 24.

Prof. Mark Thursz commented on the exciting protease inhibitor data showcased at the congress: “With genotype-1 the most common and most challenging type of HCV to cure, both studies have demonstrated extremely encouraging results with cleaner profiles than existing protease inhibitors. It is unlikely telaprevir and boceprevir will remain in the hepatic armoury for much longer.”

“We truly are in a prime time for HCV therapy; these effective new treatment options have the potential to pave the way for future interferon-sparing regimens and we look forward to using them in the clinic” added Prof Thursz.

Other promising Phase II data presented at the congress may provide further options:

ELECTRON

Results of the ELECTRON study6 show that all-oral regimens containing sofosbuvir in combination with a second DAA and ribavirin show promising efficacy, with rapid and consistent antiviral suppression in both treatment-naïve patients and prior null responders. High response rates in those treatment arms employing a second agent supports the hypothesis that the addition of another DAA with a different mechanism of action and non-overlapping resistance profile would improve rates of SVR.

IFN and RBV Free Regimen

Interim analysis of a Phase II study7 show that an interferon (IFN)- and ribavirin (RBV)-free regimen of daclatasvir (NS5A inhibitor), asunaprevir (protease inhibitor) and BMS-791325 (non-nucleoside NS5B inhibitor) achieved, overall, an SVR4 of 92% (46/50), SVR12 of 94% (30/32), and SVR24 of 94% (15/16) in treatment-naive genotype (GT) 1 patients, mainly GT1a and IL28B non-CC. Patients were initially randomised (1:1) to daclatasvir 60mg QD, asunaprevir 200mg BID, and BMS-791325 75mg BID for a period of 24 or 12 weeks. Following one month of safety observation, a second cohort was randomized (1:1) to the same regimen but including BMS-791325 150mg BID (24 or 12 weeks). The primary end point was HCV RNA < 25 IU/mL at 12 weeks post-treatment (SVR12). Sixty four of the 66 patients had a HCV RNA < 25 IU/mL by week 4, with no difference in virological responses between 12 and 24 weeks of treatment.

AVIATOR

Latest results from the AVIATOR study8, using a combination of ABT-450/r (HCV protease inhibitor dosed with ritonavir 100 mg) with ABT-267 (NS5A inhibitor) and/or ABT-333 (non-nucleoside NS5B inhibitor) +/- ribavirin, demonstrate impressive SVR12 in patients with chronic HCV GT1 infection. The overall intention-to-treat SVR12 rate for 12-week treatment with three DAAs in combination with ribavirin was 98.7% (78/79) in treatment-naïve patients, and 93% (42/45) in null responders.

EASL Secretary General Prof. Mark Thursz commented further: “With such high success rates and increased safety and tolerability with novel DAAs, patients can be optimistic about oral treatment regimens in the not-too-distant future.”

Disclaimer: The data referenced in this release is based on the submitted abstract. More recent data may be presented at the International Liver Congress™ 2013.

References 

[1] Jacobson, I et al, TREATMENT WITH SOFOSBUVIR+RIBAVIRIN FOR 12 WEEKS ACHIEVES SVR12 OF 78% IN GT2/3 INTERFERON- INELIGIBLE, -INTOLERANT, OR -UNWILLING PATIENTS: RESULTS OF THE PHASE 3 POSITRON TRIAL. Presented at the International Liver Congress™ 2013

[2] Lawitz, E et al, SOFOSBUVIR + PEGINTERFERON + RIBAVIRIN FOR 12 WEEKS ACHIEVES 90% SVR12 IN GENOTYPE 1, 4, 5, OR 6 HCV INFECTED PATIENTS: THE NEUTRINO STUDY. Presented at the International Liver Congress™ 2013

[3] Ferenci, P et al, FALDAPREVIR PLUS PEGYLATED INTERFERON ALFA-2A AND RIBAVIRIN IN CHRONIC HCV GENOTYPE-1 TREATMENT-NAÏVE PATIENTS: FINAL RESULTS FROM STARTVERSO1, A RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE III TRIAL. Presented at the International Liver Congress™ 2013

[4] Jacobson, I et al, SIMEPREVIR (TMC435) WITH PEGINTERFERON/RIBAVIRIN FOR CHRONIC HCV GENOTYPE-1 INFECTION IN TREATMENT-NAÏVE PATIENTS; RESULTS FROM QUEST-1, A PHASE III TRIAL. Presented at the International Liver Congress™ 2013

[5] Manns M, et al, SIMEPREVIR (TMC435) WITH PEGINTERFERON/RIBAVIRIN FOR CHRONIC HCV GENOTYPE-1 INFECTION IN TREATMENT-NAÏVE PATIENTS; RESULTS FROM QUEST-2, A PHASE III TRIAL. Presented at the International Liver Congress™ 2013

[6] Gane EJ, et al, ALL-ORAL SOFOSBUVIR-BASED 12-WEEK REGIMENS FOR THE TREATMENT OF CHRONIC HCV INFECTION: THE ELECTRON STUDY Presented at the International Liver Congress™ 2013

[7] Everson, GT et al, INTERIM ANALYSIS OF AN INTERFERON (IFN)- AND RIBAVIRIN (RBV)-FREE REGIMEN OF DACLATASVIR (DCV), ASUNAPREVIR (ASV), AND BMS-791325 IN TREATMENT-NAIVE, HEPATITIS C VIRUS GENOTYPE 1-INFECTED PATIENTS. Presented at the International Liver Congress™ 2013

[8] Kowdley, KV et al, SAFETY AND EFFICACY OF INTERFERON-FREE REGIMENS OF ABT-450/R, ABT-267, ABT-333 +/- RIBAVIRIN IN PATIENTS WITH CHRONIC HCV GT1 INFECTION: RESULTS FROM THE AVIATOR STUDY. Presented at the International Liver Congress™ 2013

[9] EASL Clinical Practice Guidelines: Management of hepatitis C virus infection. European Association for the Study of the Liver. Journal of Hepatology 2011;55:245–264

[10] Hepatitis C Fact Sheet. World Health Organisation factsheet. Available at http://www.who.int/mediacentre/factsheets/fs164/en/index.html. Last accessed 28.03.13

http://virtualpressoffice.easl.eu/direct-acting-antivirals-now-ready-for-prime-time-with-promising-alternatives-on-the-way/

EASL- Phase 2b Interferon-Free Combination Studies with ABT-450 Sustains Hepatitis C Viral Response to 24 Weeks

Related: AbbVie in race with Gilead to be first to market with an all-oral treatment for hepatitis C

Medscape Medical News from the:
International Liver Congress 2013: 48th Annual Meeting of the European Association for the Study of the Liver (EASL)    

This coverage is not sanctioned by, nor a part of, the European Association for the Study of the Liver.

Medscape Medical News > Conference News

 

Oral Regimen Sustains Hepatitis C Viral Response to 24 Weeks

Daniel M. Keller, PhD

Apr 25, 2013

 

AMSTERDAM, the Netherlands — A regimen of 3 direct-acting antiviral drugs plus ritonavir and ribavirin produced sustained virologic response rates in more than 90% of a broad range of patients infected with hepatitis C 24 weeks after therapy, results from a new clinical trial show.

Kris Kowdley, MD, from the Liver Center of Excellence in the Digestive Disease Institute at Virginia Mason Medical Center in Seattle, Washington, presented the results here at the International Liver Congress 2013.

The randomized, open-label, multicenter phase 2b trial, known as Aviator, shows that the sustained virologic responses seen at 12 weeks with an all-oral interferon-free regimen, presented last year at the annual meeting of the American Association for the Study of the Liver Diseases by Dr. Kowdley, are sustainable.

In the Aviator trial, noncirrhotic patients with genotype 1 hepatitis C virus who were treatment-naïve or had not responded to peginterferon and ribavirin were treated with combinations of direct-acting antiviral drugs with or without ribavirin for 8, 12, or 24 weeks.

The direct-acting antiviral drugs were once-daily ABT-450r (an NS3/4A protease inhibitor boosted with ritonavir), once-daily ABT-267 (an NS5A inhibitor), and twice-daily ABT-333 (a non-nucleoside NS5B inhibitor).

The 571 patients were predominantly white, and the mean age was 48 to 53 years. The majority, 59% to 71%, had hepatitis C genotype 1a, and mean baseline viral load was 6.6 log₁₀ hepatitis C RNA. Overall, 27% to 34% of treatment-naive patients had genotype IL28B CC, whereas only 2% to 4% of the null responders did.

Patients coinfected with HIV or hepatitis B were excluded from the study.

For the 79 treatment-naive patients who received the regimen consisting of 3 direct-acting antiviral drugs plus ribavirin for 12 weeks, 96% achieved sustained virologic response rates at 24 weeks (99% achieved this at 12 weeks).

High Response Rates
Response rates were no higher with 24 weeks of treatment than with 12 weeks of treatment. Even with only 8 weeks of treatment, 88% of patients achieved sustained virologic response rates at 24 weeks and 89% achieved this at 12 weeks.

For the null responders who received the triple-drug plus ribavirin regimen, 93% of the 45 patients who received 12 weeks of treatment achieved sustained virologic response, as did 95% of the 43 patients who received 24 weeks of treatment.

With the triple-drug plus ribavirin regimen, the achievement of sustained virologic response was similar in the treatment-naive and null-responder patients, regardless of sex, genotype (1a or 1b), host IL28B genotype, severity of liver fibrosis, or baseline RNA level.

Of the 247 patients who received the triple-drug plus ribavirin regimen for 12 or 24 weeks, 4 (1.6%) discontinued the study because of drug-related adverse effects.

Of 4 serious adverse effects noted in the analysis, 1 arthralgia was possibly related to therapy. More common adverse effects, reported in more than 10% of patients, were headache, fatigue, nausea, insomnia, and diarrhea. Of the patients with grade 3/4 laboratory abnormalities, 6 had elevated total bilirubin and 1 had elevated alanine aminotransferase, which resolved with continuation of the drugs.

 

Prolonging the therapy for another 12 weeks does not appear to improve the sustained virologic response.

 

Dr. Kowdley told Medscape Medical News that results from the Aviator trial highlight 2 key points. "First, prolonging the therapy for another 12 weeks does not appear to improve the sustained virologic response. Second, greater treatment exposure does not seem to increase the risk of resistance; we're not seeing a drop off or more breakthroughs, because the number of breakthroughs has remained at 0. That's a really important point."

With the triple-drug plus ribavirin regimen, which is the optimal regimen, "sustained virologic response at 24 weeks remains very durable, compared with sustained virologic response at 12 weeks. That is true in both the null responders and treatment-naive patients.... So for those patients who do end up, for whatever reason, being on 24 weeks, we can feel, I think, reasonably confident that the resistance risk is not increased," Dr. Kowdley said.

A concern all along has been the high pill burden of this all-oral regimen. Dr. Kowdley said he expects that, for upcoming trials, reformulations will combine the once-daily ABT-267, ABT-450, and ritonavir into 1 pill, while keeping the twice-daily ABT-333 and the ribavirin separate. "I would say that in the phase 3 program and going forward, the pill burden should be lower," he predicted.
The sustained virologic response for treatment-naive patients is "extremely impressive," said Mark Thursz, MD, from Imperial College in London, the United Kingdom, and secretary general of the European Association for the Study of the Liver. Similarly, for null responders, Dr. Thursz, who was not involved in the study, said he is "quite excited" by the "really high sustained virologic responses."

 

He remarked that, in general, the protease inhibitors in development to treat hepatitis C virus have "much cleaner profiles than the current ones that we're using," but he added that "it's not quite time to bury the interferon yet."

However, "the vital signs are not looking good for either boceprevir or telaprevir." In light of the drugs now in trials, "it's time to move on," Dr. Thursz said.

The study was supported by AbbVie. Dr. Kowdley reports receiving research support from AbbVie, Beckman Boehringer Ingelheim, Bristol-Myers Squibb, Gilead/Pharmasset, Ikaria, Intercept, Janssen, Merck, Mochida, Vertex, Scientific Consulting, and Novartis; and being on advisory boards for AbbVie, Gilead, Merck, and Vertex. Dr. Thursz has disclosed no relevant financial relationships.
International Liver Congress 2013: 48th Annual Meeting of the European Association for the Study of the Liver (EASL). Abstract 3. Presented April 25, 2013.

Enanta Announces New Data From Phase 2b Interferon-Free Combination Studies with Protease Inhibitor ABT-450 for Hepatitis C Treatment to be Presented at EASL

- Poster Presentations to Include Enanta’s Cyclophilin Inhibitor Program and Additional ABT-450 Data -

WATERTOWN, Mass.--(BUSINESS WIRE)--Enanta Pharmaceuticals, Inc., (NASDAQ: ENTA), a research and development-focused biotechnology company dedicated to creating small molecule drugs in the infectious disease field, announced today that new Phase 2b data related to ABT-450, Enanta’s lead HCV protease inhibitor identified in its ongoing collaboration with AbbVie, as well as new preclinical data on Enanta’s proprietary cyclophilin inhibitor, EDP-546, will be presented at the International Liver Congress, (ILC), which is the 48th Annual Meeting of the European Association for the Study of the Liver (EASL) taking place in Amsterdam April 24-28, 2013.

“Study of ABT-267 2-Day Monotherapy Followed by 12-Week Combination Therapy in Treatment Naïve Patients with Chronic HCV Genotype 1 Infection”

Results from "Aviator," AbbVie’s Phase 2b clinical trial of ABT-450 combined with two of AbbVie’s proprietary 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. SVR rates of 96% to 99% after 12 weeks of treatment were achieved in patients new to treatment (naïve) and 93% in patients who had previously failed treatment with pegylated interferon and ribavirin (null responders). In addition, similarly high SVR rates over 90% observed after 24 weeks of treatment in the Phase 2b 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 3 clinical trials. Data from the "Aviator" study will be presented during the official ILC press conference in Amsterdam on Wednesday, April 24 at 11:00 am CEST and also in an oral presentation on Thursday, April 25.

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-naïve 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:

 Click To Enlarge

For the 12-week triple-DAA regimen with ribavirin that is being studied in the Phase 3 trials, these Phase 2b Aviator data show:

• 99% of treatment-naïve 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 naïve patients and null responder patients across HCV subtype, IL28B genotype, baseline HCV-RNA levels and severity of fibrosis.
   
SVR₂₄ by patient subtype in the "Aviator" study
   

Characteristic			Treatment Naïve			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.

“Results from treatment utilizing ABT-450 in combination with other antiviral agents in AbbVie’s portfolio continue to generate high SVR rates across multiple HCV patient types,” stated Jay R. Luly, Ph.D., President and Chief Executive Officer. “These results are especially promising for those who have failed previous therapy and for those with more advanced disease.”

The focus of ABT-450 development is to study the compound in combination with other antiviral agents in AbbVie’s portfolio. The three direct acting antivirals, or triple DAA cocktail, studied in the Phase 2b interferon-free Aviator trial included ritonavir-boosted protease inhibitor ABT-450/r, non-nucleoside polymerase inhibitor ABT-333, and NS5A inhibitor ABT-267.

Abstracts for the three presentations can be viewed at the EASL website at www.easl.eu

ABT-450 containing data presentations are as follows:
Oral Presentation – Kris V. Kowdley, et al., Thursday, April 25 from 1:30 – 3:30 p.m. CEST
"Safety and Efficacy of Interferon-Free Regimens of ABT-450/r, ABT-267, ABT-333 ± ribavirin in Patients with Chronic HCV GT1 Infection: Results from the Aviator Study"
Poster # 1190 – Michael Epstein, et al., Saturday, April 27 from 12:30 – 1:30 p.m. CEST
"Study of ABT-267 2-Day Monotherapy Followed by 12-Week Combination Therapy in Treatment Naïve Patients with Chronic HCV Genotype 1 Infection"

Enanta’s proprietary cyclophilin inhibitor data presentation:
Poster #1213 – C.M. Owens, et al., Saturday, April 27 from 9:00 a.m. – 6:00 p.m. CEST
"Cyclophilin Inhibitor EDP-546 is a Potential Cornerstone Drug for Use in Combination with NS5A and Protease Inhibitors Due to Its High Barrier to Resistance"

“We continue to advance our lead cyclophilin candidates in preclinical studies and are continuing to generate and characterize a number of additional candidates,” commented Yat Sun Or, Ph.D., Senior Vice President and Chief Scientific Officer. “We expect to select a preclinical candidate to advance during 2013.”

About Hepatitis C Virus (HCV)

Hepatitis C is a liver disease affecting over 170 million people worldwide. The virus is typically spread through direct contact with the blood of an infected person. Hepatitis C increases a person’s risk of developing chronic liver disease, cirrhosis, liver cancer and death. There is an acute need for new HCV therapies that are safer and more effective for many variants of the virus.

Collaboration with AbbVie (formerly the research-based pharmaceutical business of Abbott Labs)

In December 2006, Enanta and Abbott announced a worldwide agreement to collaborate on the discovery, development and commercialization of HCV NS3 and NS3/4A protease inhibitors and HCV protease inhibitor-containing drug combinations. Under the agreement, AbbVie is responsible for all development and commercialization activities for ABT-450, the program’s lead compound. Enanta received a $57 million upfront payment upon signing the collaboration agreement and is eligible to receive additional pre-commercial milestones, as well as double-digit royalties on any revenue allocable to the collaboration’s protease inhibitors. Also, for any additional collaborative HCV protease inhibitor product candidate developed under the agreement, Enanta holds an option to fund 40 percent of U.S. development costs and U.S. commercialization efforts (sales and promotion costs) in exchange for 40 percent of any U.S. profits ultimately achieved after regulatory approval.

About Enanta

Enanta Pharmaceuticals is a research and development-focused biotechnology company that uses its robust chemistry-driven approach and drug discovery capabilities to create small molecule drugs in the infectious disease field. Enanta is discovering and developing novel inhibitors designed for use against the hepatitis C virus (HCV). These inhibitors include members of the direct acting antiviral (DAA) inhibitor classes – protease (partnered with AbbVie), NS5A (partnered with Novartis) and nucleotide polymerase – as well as a host-targeted antiviral (HTA) inhibitor class targeted against cyclophilin. Additionally, Enanta has created a new class of antibiotics, called Bicyclolides, for the treatment of multi-drug resistant bacteria, with a current focus on developing an intravenous and oral treatment for hospital and community MRSA (methicillin-resistant Staphylococcus aureus) infections.

Forward Looking Statement

This press release contains forward-looking statements, including with respect to our expectation that we will select a preclinical cyclophilin inhibitor candidate to advance to clinical trials during 2013 and expectations regarding the successful completion of clinical development of ABT-450. Statements that are not historical facts are based on our management’s current expectations, estimates, forecasts and projections about our business and the industry in which we operate and our management’s beliefs and assumptions. The statements contained in this release are not guarantees of future performance and involve certain risks, uncertainties and assumptions, which are difficult to predict. Therefore, actual outcomes and results may differ materially from what is expressed in such forward-looking statements. Important factors that may affect actual results include our ability to successfully identify appropriate candidates for clinical development of our future product candidates, the development efforts of our collaborators, regulatory actions affecting clinical development and clinical development of competitive product candidates. Enanta cautions investors not to place undue reliance on the forward-looking statements contained in this release. These statements speak only as of the date of this release, and Enanta undertakes no obligation to update or revise these statements, except as may be required by law.

Contacts

Investor Contact
Enanta Pharmaceuticals, Inc.
Carol Miceli, 617-607-0710
cmiceli@enanta.com
or
Media Contact
MacDougall Biomedical Communications
Kari Watson or Charles Liles, 781-235-3060
kwatson@macbiocom.com or cliles@macbiocom.com

AbbVie in race with Gilead to be first to market with an all-oral treatment for hepatitis C

AbbVie hepatitis C drugs knock out virus at eight weeks


Tuesday Apr 23, 2013 |   Ransdell Pierson, Bill Berkrot for Reuters

(Reuters) - A combination of five oral drugs being tested by AbbVie Inc cured at least 88 percent of new patients with hepatitis C after only eight weeks of treatment, without raising significant safety issues, researchers said on Tuesday.

The latest findings from an ongoing trial sponsored by AbbVie, called Aviator, also showed that 96 percent of patients taking the five medicines for 12 weeks eliminated the virus, as assessed by blood tests 24 weeks after they stopped treatment.

If the virus is undetectable 24 weeks after completing treatment, known as SVR 24, a patient is considered cured.

The latest results were deemed little different than the 99 percent sustained virologic response (SVR) rate reported in October, for patients evaluated 12 weeks after completing 12 weeks of the five-drug treatment regimen.

"We are pleased that the data remain consistent and robust," said Dr. Kris Kowdley, who is presenting the data this week at a meeting of the European Association for the Study of the Liver (EASL) in Amsterdam.

"The data confirm that the 12-week treatment appears to be optimal, but certainly we are still very pleased with ... data for the eight-week treatment," Kowdley said in an interview.

AbbVie is deemed to be in a horse race with Gilead Sciences Inc to be first to market with an all-oral treatment for the serious liver disease, as companies work to eliminate difficult-to-tolerate intravenous interferon from the regimen, while raising cure rates and shortening treatment duration.

Current hepatitis C treatments take either 24 or 48 weeks.

Hepatitis C affects an estimated 170 million people worldwide, and if left untreated can lead to cirrhosis, liver cancer or the need for a new liver.

Gilead has been given an edge by many analysts because its experimental regimen involves fewer drugs. But Abbvie said it is also testing regimens with fewer drugs and ones that do not include the older oral drug ribavirin, which can also be difficult for some patients to tolerate.

Any oral regimen to treat hepatitis C is expected to garner billions of dollars in annual sales.

Patients in the Aviator study had the most common, but hardest to treat, genotype 1 variation of the infectious virus. The AbbVie drugs were the protease inhibitor ABT-450, whose effect was boosted by a widely used antiviral called ritonavir; the polymerase inhibitor ABT-333 and ABT-267 from a class known as NS5A inhibitors. Those were given along with the generic antiviral medicine, ribavirin.

Kowdley, director of the Liver Center of Excellence at Virginia Mason Medical Center in Seattle, said the trial also showed impressive results among patients who had failed to benefit from earlier therapy.

The cure rate after 12 weeks of treatment was 93 percent for those patients, called null responders, assessed both 12 weeks and 24 weeks after completion of their drug regimens. That compared with a cure rate of 95 percent for patients treated for 24 weeks, and then assessed 24 weeks after treatment stopped.

AbbVie said the safety of the tested drugs was similar to that seen in results presented last year. Of the 247 patients evaluated, serious side effects were seen in four patients (1.6 percent), while seven patients had elevated levels of liver enzymes that can be considered a potential sign of toxicity.

Less serious side effects seen in more than 10 percent of patients included headache, fatigue, nausea, insomnia and diarrhea.

(Editing by Jan Paschal)

Interferon-Free Therapies for Hep C Virus Look Promising

New Pills Show Promise for Hepatitis C

If approved, they'll provide fewer side effects, shorter treatment time, studies suggest

WEDNESDAY, Jan. 2 (HealthDay News) -- Two new pills on the horizon for people with hepatitis C promise shorter treatment time and fewer side effects than today's standard treatment, interferon.
The first treatment studied combines a drug currently called ABT-450/r and one called ABT-333. Together, these drugs achieved up to a 95 percent sustained response, meaning the drugs suppressed levels of hepatitis C in the blood over time.

The second drug, called sofosbuvir, when combined with the currently used medication ribavirin, induced a 100 percent sustained response rate, the researchers found.

Both drugs require just 12 weeks of treatment compared to today's standard of 48 weeks, according to the authors.

"Over the next few years, we're going to have several new options to eradicate the hepatitis C virus," said the lead author of the ABT-450/r study, Dr. Fred Poordad, a professor of medicine at the University of Texas Health Science Center in San Antonio.

"We're hopeful that in the next 10 years, we should be able to eradicate hepatitis C in most Americans," said Poordad.

Both studies appear in the Jan. 3 issue of the New England Journal of Medicine. The ABT-450/r study was funded by the drug maker, Abbott Pharmaceuticals, and the sofosbuvir study was funded by drug makers Pharmasset and Gilead Sciences.

More than 3 million Americans have hepatitis C, a contagious liver disease usually spread through contact with the blood of someone already infected, according to the U.S. Centers for Disease Control and Prevention. The infection can be either acute or chronic. Chronic hepatitis C can scar the liver and eventually lead to liver failure. Poordad said it's one of the most common reasons for a liver transplant.

The current treatment combines two medications: interferon and ribavirin. Interferon is only available by injection, and must be administered three times a week for 48 weeks. Ribavirin is a pill. Side effects of interferon, which can last the duration of treatment, include flu-like symptoms, such as fever, chills, muscle aches and headache.

Poordad explained that this is because interferon dampens the whole immune system to keep the virus at bay. The new medications are what's called targeted therapies, which specifically go after the hepatitis C virus instead of attacking the whole immune system, he said.

"We're giving a drug that's killing the virus without bothering the host (the person with hepatitis C)," said Poordad.

His study had 50 people with genotype 1 hepatitis C, the most common and hardest-to-treat form of hepatitis C, according to Poordad. None had developed liver scarring (cirrhosis) yet.

Study volunteers were split into three groups. One group had never been treated for hepatitis C and received ABT-333, ribavirin and 250 milligrams (mg) of ABT-450 with 100 mg of ritonavir (making the ABT-450/r combination). The second group had also never received treatment. They received the same medications, except their dose of ABT-450 was 150 mg. The third group had received treatment for hepatitis C but had had no response or only a partial response to treatment. They were given ABT-333, ribavirin and 150 mg of ABT-450 and 100 mg of ritonavir.

The first two groups had a 95 percent and 93 percent sustained response to the drug. In the third group, only 47 percent had a sustained virologic response, the investigators found.
The most common side effects included abnormal liver function tests, fatigue, nausea, itching and headache.

The second study, conducted in New Zealand, included 95 people with hepatitis C genotypes 1, 2 or 3. They were split into eight groups and received varying treatments. All of the treatments included 400 mg of the new drug sofosbuvir.

Sustained response rates were impressive -- 100 percent -- when sofosbuvir was combined with ribavirin, or with interferon for people with genotypes 2 and 3. When sofosbuvir was given alone, it achieved a sustained response rate of 60 percent for those with genotypes 2 and 3.

For those with genotype 1 who had never received treatment, sofosbuvir and ribavirin achieved an 84 percent sustained response. For those who hadn't responded to prior treatment, this combination resulted in just a 10 percent sustained viral response rate.

Like ABT-450/r, the side effects for sofosbuvir included headache, fatigue, nausea and skin rash.
Experts welcomed the findings.

"Overall, these results are encouraging, and there's definitely a need for new treatments," said liver specialist Dr. Natasha Von Roenn, from Loyola University Medical Center in Chicago.
"Headache seemed to be a significant side effect in both studies, but the good news was that none of the patients had to stop treatment because of side effects," she noted.
"We're moving closer to having an oral interferon-free regimen with good response rates," she added.
Both studies were phase 2 studies, so neither treatment is yet available.

More information
Learn more about hepatitis C and its treatment from the U.S. Centers for Disease Control and Prevention.

http://www.ivillage.com/new-pills-show-promise-hepatitis-c/4-a-512426

Interferon-Free Therapies for Hep C Virus Look Promising Sofosbuvir plus ribavirin and ABT-450/ritonavir, ABT-333, ribavirin combos seem effective WEDNESDAY, Jan 2 HealthDay News- For untreated patients with hepatitis C virus (HCV), treatment with an oral nucleotide inhibitor of HCV polymerase, sofosbuvir, plus ribavirin seems effective for genotypes 1, 2, and 3; and the HCV NS3 protease inhibitor ABT-450, combined with low-dose ritonavir (ABT-450/r) plus the nonnucleoside NS5B polymerase inhibitor ABT-333 and ribavirin, seems effective for genotype 1, according to two studies published in the Jan. 2 issue of the New England Journal of Medicine. Edward J. Gane, M.D., from Auckland City Hospital in New Zealand, and colleagues evaluated sofosbuvir in interferon-sparing and interferon-free regimens for patients with untreated HCV genotype 2 and 3. After 24 weeks of therapy, the researchers found that all patients who received sofosbuvir plus ribavirin without interferon or with interferon had a sustained virologic response. In addition, 84 percent of previously untreated patients with HCV genotype 1 had a sustained virologic response with sofosbuvir and ribavirin. In a second study, Fred Poordad, M.D., from the University of Texas Health Science Center in San Antonio, and colleagues assessed the role of ABT-450/r, ABT-333, and ribavirin for treatment of HCV 1 infection without cirrhosis in a 12-week phase 2a study. The researchers found that most untreated patients had an extended rapid virologic response, and 93 to 95 percent had a sustained virologic response 12 weeks after the end of treatment. Forty-seven percent of those who had had a null or partial response to previous therapy with peginterferon and ribavirin had sustained virologic response 12 weeks after therapy. "This preliminary study suggests that 12 weeks of therapy with a combination of a protease inhibitor, a nonnucleoside polymerase inhibitor, and ribavirin may be effective for treatment of HCV genotype 1 infection," Poordad and colleagues conclude. The Gane study was supported by Pharmasset and Gilead Sciences; the Poordad study was funded by Abbott. Full Text - Gane (subscription or payment may be required) Full Text - Poordad (subscription or payment may be required)

AASLD- Interferon-Free Regimens Produce High HCV Sustained Response

Medscape Medical News from:
The Liver Meeting 2012: American Association for the Study of Liver Diseases (AASLD) 63rd Annual Meeting

This coverage is not sanctioned by, nor a part of, the American Association for the Study of Liver Diseases.

Medscape Medical News > Conference News

Interferon-Free Regimens Produce High HCV Sustained Response

BOSTON — A phase 2b trial of an oral, interferon-free regimen of 3 direct-acting antiviral drugs (DAAs) has shown very good efficacy in the treatment of hepatitis C virus (HCV) infection in both treatment-naive patients and null responders.
       
Speaking here at Liver Meeting 2012: American Association for the Study of Liver Diseases 63rd Annual Meeting, lead author Kris Kowdley, MD, of the Liver Center of Excellence in the Digestive Disease Institute at Virginia Mason Medical Center and a clinical professor of medicine at the University of Washington in Seattle, said that because of the high pill burden, 2 of the drugs (with ribavirin) will be formulated into a single tablet for phase 3 trials.
       
The all-oral treatment regimen consisted of ABT-450 (a daily NS3/4A protease inhibitor) boosted with ritonavir (ABT-450/r), ABT-267 (a daily NS5A inhibitor), and ABT-333 (a twice-daily nonnucleoside polymerase inhibitor) with or without ribavirin. Eligible patients (N = 448) were aged 18 to 70 years, had chronic HCV genotype 1 (GT1) infection regardless of IL28B host genotype, were noncirrhotic, were either treatment-naive or had not responded to prior treatment with peg-interferon and ribavirin (null responders), and were not coinfected with either HIV or hepatitis B virus.
       
All groups of patients were about 55% to 62% male (except 1 group, which was 44% male), predominantly white, and about 50 years old on average. Of the treatment-naive patients, 26% to 29% were of IL28B CC genotype, whereas only 2% to 4% of the null responders were. In all the treatment groups, 59% to 71% of the patients were infected with HCV genotype 1a, and mean baseline log₁₀ HCV RNA levels were about 6.6.
       
Treatment was for 8, 12, or 24 weeks with ABT-450/r with various combinations of the other ABT drugs, with or without ribavirin for treatment-naive patients. Null responders received all 3 drugs or ABT-450/r and ABT-267 for 12 weeks, or all 3 drugs for 24 weeks, always with ribavirin.
The primary and secondary efficacy endpoints were sustained viral response at 24 weeks (SVR₂₄). Those results will be presented at a later time. Dr. Kowdley presented sustained viral response at 12 weeks (SVR₁₂) here.
       
Very High Response Rates, Especially With Ribavirin
For the 8- and 12-week groups, "regardless of treatment assignment, very high rates of SVR₁₂ were reached across all categories both in the treatment-naive and nonresponder [null responder] categories," Dr. Kowdley reported. "But in particular, the group receiving 3 DAAs and ribavirin showed the highest SVR₁₂ rates."
       
Treatment-naive patients treated for either 8 or 12 weeks achieved 85.4% to 97.5% SVR₁₂ on an intent-to-treat basis, with the highest response rates achieved with 12-week regimens of ABT-450/r, ABT-267, and ribavirin (89.9%) or ABT-450/r, ABT-267, ABT-333, and ribavirin (97.5%).
For null responders treated for 12 weeks, the SVR₁₂ response rate was 88.9% with ABT-450/r, ABT-267, and ribavirin and 93.3% with all 3 DAAs plus ribavirin. Null responders have historically been resistant to retreatment, with only about 30% responding to peg-interferon and ribavirin.
Treatment-naive patients with HCV GT1a treated for 12 weeks responded only slightly less well (82% - 98%) than the GT1b-infected patients (100% SVR₁₂ regardless of drug combination). GT1a null responders had 81% to 89% responses, but 100% of the GT1b-infected null responders achieved an SVR₁₂.
       
The safety and tolerability of the regimens were excellent. One percent of the 448 patients in the trial discontinued it because of adverse events (AEs). Of 5 serious AEs, 1 case of arthralgia was possibly related to study drugs. The most common AEs were fatigue, headache, nausea, and insomnia affecting treatment-naive patients and null responders. Of 2 patients whose study drugs were discontinued by an investigator because of AEs attributed to the drugs, the AEs resolved, and both patients achieved a sustained viral response.
       
Very few clinical chemistry or hematologic abnormalities occurred. The most common ones were transient indirect bilirubin increases twice the upper limit of normal or greater in 6.7% and 12.2% of the treatment-naive patients and null responders, respectively. As expected, there was significantly less decrease in hemoglobin in the ribavirin-free regimens.
       
Drug Combination Can Overcome Barriers to Effective Treatment
In summary, Dr. Kowdley said the 12-week, 3-DAA regimens with ribavirin showed the greatest efficacy in both treatment-naive patients and null responders, for both GT1a and GT1b infections, and across all IL28B host genotypes. All of the drug combinations were well tolerated in the 8- and 12-week treatment groups.
       
The 3-DAA regimen with and without ribavirin will move into phase 3 testing with a coformulated tablet of ABT-450/ritonavir/ABT-267 to reduce the pill burden, Dr. Kowdley said.
Mark Thursz, MBBS, MD, professor of hepatology in the Department of Medicine at Imperial College, London, UK, and secretary general of the European Association for the Study of the Liver, commented to Medscape Medical News that the data from the trial is "impressive both in naive patients and in patients who were previous null responders."
       
He said 2 important points to note are that IL28 host genotype does not appear to matter, "as there were good responses in all 3 genotypes." Second, "the combination appears to be equally effective against HCV GT1a and 1b whereas 1a has been a problem in other studies."
       
But Dr. Thursz pointed out that on the downside, patients have to take 5 medications to get the best efficacy from these drugs. "Also worth noting is that SVRs were less frequent in the 8-week treatment arms vs the 12 weeks," he said. "As with many other [interferon] regimens, 12 or 24 weeks' treatment seems to be a requirement."
       
Paul Pockros, MD, director of the Liver Disease Center and senior consultant in the Division of Gastroenterology/Hepatology at Scripps Clinic in La Jolla, California, commented to Medscape Medical News that the data from this study look very good and show that the drug combination can overcome some long-standing barriers to effective treatment.
       
"Before, many of the regimens [containing DAAs] we've seen have all been more effective in genotype 1b than 1a, so genotype 1a was a barrier, and in this study they overcame that. The efficacy was very, very high in both 1a and 1b," he said.
       
"Number 2, they were able to shorten therapy to 12 weeks." Dr. Pockros said the drugs' developer is also going to explore an even shorter regimen of 8 weeks.
       
"Number 3, they overcame the barrier of nonresponse, so they had true null responders" in the study, defined as patients who did not have a 2-log₁₀ drop in HCV RNA with 12 weeks of peg-interferon/ribavirin. "That's a difficult treatment group, and with telaprevir, their SVR rates are only 30% or 35%, same with boceprevir," he said. "So this overcame that barrier, and the SVR rates were [93.3%] in the null responders with an intention-to-treat analysis, so that's really great data."
Dr. Pockros expressed concern about a burden of 5 pills a day but noted that with a reformulated pill containing ABT-450/r/ABT-267, "that's going to be 1 pill, and that's no longer a deal breaker," taken with ABT-333 and maybe with ribavirin.
       
"There may be patients you can just give that to as a single capsule, which would make them very competitive with [a combination treatment from] Gilead, for instance, if they have a single-formulated compound," he predicted.
       
The next key step will be to do the same study in a population of cirrhotic patients, which investigators will initiate soon. Dr. Pockros said that if patients with cirrhosis could achieve an 80% SVR rate, "that would be a win."
       
The study was supported by Abbott Laboratories. Dr. Kowdley has research support from Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead/Pharmasset, Intercept, Janssen, Merck, Mochida, Vertex, Scientific Consulting, and Novartis. He is on advisory boards for Abbott, Gilead, Merck, and Vertex. Dr. Pockros does studies for Gilead, BMS, and Abbott, is a speaker for BMS, and is an advisor to all 3.

The Liver Meeting 2012: American Association for the Study of Liver Diseases 63rd Annual Meeting. Abstract LB-1. Presented November 12, 2012.

Medscape AASLD Coverage

Interferon-Free Regimens Produce High HCV Sustained Response

Medscape Medical News, November 13, 2012

 

AASLD Healthcare Workers May Need HBV Boosters as Titers Drop

Medscape Medical News, November 12, 2012

AASLD Novartis' Certican Succeeds in Liver Transplant Trial

Reuters Health Information, November 12, 2012

AASLD Sarcopenia Does Not Raise Liver Transplant Mortality Risk

Medscape Medical News, November 11, 2012

AASLD - Drug Combos Hit Hep C Virus Hard

Drug Combos Hit Hep C Virus Hard

By Michael Smith, North American Correspondent, MedPage Today

Published: November 13, 2012
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston

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.

Explain that a trial that included arms with five direct antiviral drugs but no interferon successfully achieved sustained virologic response (SVR) at 12 weeks in hepatitis C-infected patients with genotype 1 infection.

Note that SVR12 response rates were uniformly high, whether patients were treatment-naive or they had failed previous interferon-plus-ribavirin standard therapy

BOSTON – A series of all-oral regimens for hepatitis C -- with four or five drugs each but without interferon -- yielded response rates of greater than 85% in difficult-to-treat patients, a researcher reported here.

For two of the regimens, the so-called sustained virologic response (SVR) 12 weeks after the end of treatment was between 93% and 98%, according to Kris Kowdley, MD, of Virginia Mason Medical Center in Seattle.

Those results were obtained, respectively, in a group of people who failed to respond to previous treatment with pegylated interferon and ribavirin (the standard therapy), and in people who had never been treated for the virus, Kowdley reported in the late-breaker session at the annual meeting of the American Association for the Study of Liver Diseases.

The researchers were studying combinations of three so-called direct-acting agents – they target the hepatitis C virus itself – with or without ribavirin, which interferes with replication of many viruses.
One of the direct-acting agents, dubbed ABT-450, is a protease inhibitor that must be boosted with ritonavir (Norvir), much as some anti-HIV drugs are boosted.

The others are ABT-267, which blocks the viral nonstructural protein NS5A, and ABT-333, a non-nucleoside polymerase inhibitor.

The goal of the industry-sponsored study was to define optimal regimens to treat people with genotype 1 virus who had not previously been treated and those who had not responded to interferon and ribavirin previously.

All told, the study has nine arms, with treatment durations ranging from 8 to 24 weeks, and the primary endpoint is sustained virologic response 24 weeks (SVR₂₄) after the end of treatment.
Sustained virologic response means that the virus is not detectable at the time of the measurement; an SVR₂₄ is widely regarded as a cure.

Kowdley presented the 12-week SVR data – dubbed SVR₁₂ -- for just the arms with treatment lasting 8 and 12 weeks.

"Regardless of treatment assignment," he said, "very high rates of SVR₁₂ were reached across all categories."

Specifically:

• The 8-week arm had 80 treatment-naive patients treated with all five drugs. On an intent-to-treat basis, the SVR₁₂ rate was 87.5%.
• The rate in the five-drug 12-week arm, with 79 treatment-naive patients, was 97.5%.
• Three other 12-week arms (with a total of 199 treatment-naive patients) all included boosted ABT-450, but each dropped one other drug -- ABT-267, ABT-333, or ribavirin. SVR₁₂ rates were 85.4%, 89.9% or 87.3%, respectively.
• In the null responders, treatment with all five drugs yielded an SVR₁₂ rate of 93.3%, while dropping ABT-333 lowered the rate to 88.9%. There were 45 patients in each arm.

When the researchers broke down the data by viral subtype, they found that SVR₁₂ rates were 100% for patients with genotype 1b, except for the 8-week treatment arm, where the rate was 96%.
Genotype 1b is considered easier to treat than 1a but even for patients with the latter genotype, SVR₁₂ rates were still high – ranging from 81% to 98%.

Interestingly, the two highest rates among patients with genotype 1a -- 98% and 89% -- were associated with all five drugs given for 12 weeks in treatment-naive and null responders, respectively, Kowdley reported.

All the regimens were well tolerated, Kowdley reported, and there were no serious adverse events related to the study drugs. The arms without ribavirin had, as expected, significantly smaller declines in hemoglobin.

Phase III trials are planned, he concluded, that will test the three direct-acting agents with or without ribavirin, but to limit the pill burden, three of the drugs – ritonavir, ABT-450, and ABT-267 – will be co-formulated in a single, once-daily pill.

Overall, "the data look very good," commented Paul Pockros, MD, of Scripps Clinic in La Jolla, Calif., who was not involved in the study.
The researchers got good results regardless of several "barriers" that had derailed previous approaches, Pockros told MedPage Today.

For instance, he noted, "efficacy was very, very high" both in hard-to-treat patients with viral genotype 1a and in those with genotype 1b.

In addition, he said, the study had good results in "a very difficult treatment group" -- those who had not responded to previous therapy with interferon and ribavirin.

On the other hand, the regimens in the study had a heavy pill burden. "Five pills is a lot of medicine," Pockros said, especially when some must be given twice a day. But plans to co-formulate some of the drugs into a single pill will eliminate that hurdle, he said.

Primary source: American Association for the Study of Liver Diseases

Source reference:
Kowdley KV, et al "A 12-week interferon-free treatment regimen with ABT-450/r, ABT-267, ABT-333 and ribavirin achieves SVR12 rates (observed data) Of 99% in treatment-naïve patients and 93% in prior null responders with HCV genotype 1 infection" AASLD 2012; Abstract LB-1.

The study was supported by Abbott. Kowdley reported financial links with the company, as well as with Boehringer Ingelheim, BMS, Gilead/Pharmasset, Intercept, Janssen, Merck, Mochida, Vertex, and Novartis. Pockros reported financial links with Novartis, Tibotec, GlobeImmune, Genentech, Merck, BMS, Gilead, Vertex, Three Rivers Pharmaceuticals, Debio, Pfizer, Conatus Pharmaceuticals, Abbott, and Mochida Pharmaceutical.

AASLD Coverage @ Medpage Today

11/13/2012
BOSTON -- Non-alcoholic fatty liver disease is an independent risk factor for hepatocellular carcinoma, even in the absence of cirrhosis, a researcher reported. more

HCV Drug Combo Promising All on Its Own
11/13/2012
BOSTON -- A three-drug regimen that eliminated both standard hepatitis C drugs has yielded positive early results in hard-to-treat patients, a researcher reported. more

Some Kids with CF Face Early Liver Disease
11/12/2012
BOSTON -- The development of cirrhosis in children with cystic fibrosis might occur sooner than expected, a researcher reported. more

HBV Drugs Cut Risk of Cancer Recurrence
11/12/2012
BOSTON -- Antiviral therapy after surgery appears to reduce the risk of recurrence of hepatocellular carcinoma related to hepatitis B, a researcher reported here. more

Antiviral Drug Cuts Cancer Risk in Hepatitis B
11/12/2012
BOSTON -- For patients with chronic hepatitis B, long-term treatment with entecavir (Baraclude) significantly cut the risk of liver cancer, researchers reported. more

Abbott Announces Phase 3 Interferon-free Hepatitis C Regimens to be Studied in Broad Patient Populations

Related- AASLD- Abbott hepatitis C oral drugs bring high cure rates in trial

Abbott Announces Phase 3 Hepatitis C Program Details

Interferon-free Hepatitis C Regimens will be Studied in Broad Patient Populations across Multiple Countries

Date: November 13, 2012

Abbott Park, Illinois (NYSE: ABT) — Abbott today released details on its phase 3 hepatitis C registrational program following promising results from its phase 2b clinical trial, known as Aviator, presented at the Annual Meeting of the American Association for the Study of Liver Disease (AASLD) in Boston. The phase 3 clinical trials are designed to evaluate safety and efficacy of a 12-week regimen of three direct acting antivirals (DAA), with and without ribavirin, for the treatment of HCV in genotype 1 (GT1) non-cirrhotic, treatment-naïve and treatment-experienced patients. An additional phase 3 trial will study triple-DAAs, with ribavirin, in patients with cirrhosis for 12 or 24 weeks.

The phase 3 program, which is currently open for enrollment, will include more than 2,000 patients with HCV genotype 1, with trial sites in 29 countries. 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 12 weeks in non-cirrhotic patients, and 12 or 24 weeks in cirrhotic patients. All patients will be followed for 48 weeks post-treatment. Co-formulated tablets of ABT-450/r and ABT-267 will be used in the phase 3 trials.
More information on the trials is available at www.clinicaltrials.gov.

"Abbott is committed to investigating a short-course HCV therapy without the use of interferon to achieve high SVR rates," said Scott Brun, M.D., divisional vice president, Infectious Disease Development, Abbott. "Our trial enrollment strives to reflect a broad range of populations, including those that have been difficult to treat. We have been very encouraged by the data from the phase 2 studies, and look forward to confirming the findings in our phase 3 program."

Topline intent-to-treat results from the 12-week, triple-DAA regimens with ribavirin presented at the AASLD meeting this week found that 97.5 percent (77 of 79) of treatment-naïve GT1 patients and 93.3 percent (42 of 45) in GT1 null responder patients achieved SVR₁₂.

About the Hepatitis C Virus
Hepatitis C is a liver disease affecting as many as 170 million people worldwide. The virus is primarily spread through direct contact with the blood of an infected person. HCV increases a person's risk of developing chronic liver disease, cirrhosis, liver cancer and death; and liver disease associated with HCV infection is growing rapidly.

Of the six main genotypes of hepatitis C, genotypes 1, 2 and 3 are the most widespread. Genotype 1 is the most common genotype in the U.S. and the most difficult to treat with interferon based therapies. Patients with genotypes 2 and 3 are more likely than individuals with genotype 1 to respond to therapy with peg-interferon or the combination of peg-interferon and ribavirin.

About Abbott's HCV Development Programs
Abbott'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 (non-therapeutic) 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 Abbott and Enanta Pharmaceuticals for HCV protease inhibitors and regimens that include protease inhibitors. ABT-450 is being developed by Abbott for use in combination with Abbott's other investigational medicines for the treatment of HCV. Abbott is well-positioned to explore combinations and co-formulations of these medicines.

Ritonavir Use in 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.

For more information, please see the Important Safety Information and Full Prescribing Information for Ritonavir.

About Abbott
Abbott (NYSE: ABT) is a global, broad-based health care company devoted to the discovery, development, manufacturing and marketing of pharmaceuticals and medical products, including nutritionals, devices and diagnostics. The company employs approximately 91,000 people and markets its products in more than 130 countries.

---

Media: Tracy Sorrentino Roseanne Durril	(847) 937-8712 (847) 938-6114
Financial: Larry Peepo Liz Shea	(847) 935-6722 (847) 935-2211