All-Oral Regimens Work in HCV

All-Oral Regimens Work in HCV

By Michael Smith, North American Correspondent, MedPage Today

Published: March 05, 2013
Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania

ATLANTA – All-oral regimens under investigation for hepatitis C virus (HCV) were able to cure up to 95% of patients who had never been treated for the virus, a researcher said here.

Action Points

Note that 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.

Note that in these two open label studies, excellent HCV cure rates were attainable in treatment-naive patients using various all-oral regimens.

Be aware that cure rates were significantly worse in patients who had failed prior therapy.

But in combined 48-week data from two small clinical trials, only 47% of people who had previously had unsuccessful HCV therapy were cured, according to Eric Lawitz, MD, of the University of Texas Health Science Center in San Antonio.

On the other hand, treatment only lasted 12 weeks, the regimens were well-tolerated, and the handful of relapses took place soon after the end of therapy, Lawitz reported at the Conference on Retroviruses and Opportunistic Infections.

The key element of the trials – which actually tested two slightly different 4-drug regimens – was that patients were not given pegylated interferon, a backbone of standard HCV therapy that is difficult to tolerate and has dangerous side effects.

"We're in a state of paradigm shift," Lawitz told reporters before presenting the data, "in transition from interferon to the era of DAAs" – direct-acting agents that target HCV directly, rather than boosting the immune system, as interferon does.

His analysis looked at outcomes after treatment with regimens based on ribavirin and ABT-450, an NS3/4A protease inhibitor that is co-administered with ritonavir (Norvir). The drugs were combined with one of two non-nucleoside inhibitors of the HCV NS5B polymerase, ABT-072 or ABT-333.

The initial trial included 11 treatment-naïve patients with genotype 1 HCV, who were given 12 weeks of therapy with ribavirin, ABT-450/ribavirin, and ABT-072.

The second trial substituted ABT-333 for ABT-072 and had three cohorts – two with treatment-naïve patients who got different doses of ABT-333 (150 or 250 milligrams daily), and one with people who had previously failed interferon-based therapy, who also got the lower dose of ABT-333.

The primary endpoint was the 24-week sustained virologic response (SVR24) -- the proportion of patients with undetectable virus 24 weeks after the end of therapy – that is usually regarded as a cure.

In the first trial, Lawitz reported that 91% of the patients reached the SVR24. In the second, the two treatment-naïve cohorts had SVR24 rates of 95% and 86%, while just 47% of those who had previously failed therapy before reached the milestone.

The IL28B polymorphism, which has variants that confer a greater risk of failing therapy, had no effect, Lawitz reported. Of the eight patients who relapsed, only two were among the treatment-naïve group and only one relapsed more than 12 weeks after the end of therapy, he reported.

There were no deaths or serious adverse events, he said, although one adverse event – an asymptomatic elevation in liver enzymes without any increase in bilirubin -- led to premature discontinuation by a treatment-naïve patient. The liver enzymes returned to normal after the drugs were stopped.

In addition, four patients had adverse events assessed as severe – hyperbilirubinemia, fatigue, pain, and vomiting – but none required interrupting the study drugs or stopping treatment, Lawitz reported.

One implication of the study might be that treating sicker patients will require more drugs or more time than treating people with less severe disease, commented Juergen Rockstroh, MD, of the University of Bonn, who was not involved in the study but who moderated the session at which it was presented.

"For easy-to-treat patients, two drugs (and ribavirin) will be just fine," he told MedPage Today. But in the previous null responders, he noted, less than half of the patients were cured.

"This is really saying that we're going to have interferon-free treatment for basically everyone who's treatment-naïve," Rockstroh said. What Lawitz's data suggest, he added, is that a more aggressive strategy will be needed for everyone else.

Primary source: Conference on Retroviruses and Opportunistic Infections
Source reference:
Lawitz E, et al "12 weeks of ABT-450/Ritonavir, non-nucleoside inhibitor and ribavirin achieved SVR24 in >90% of treatment-naive Hepatitis C Virus GT1 patients and 47% of prior non-responders" CROI 2013; Abstract 38.

The study was supported by Abbott. Lawitz reported financial links with Abbott, Achillion, Boehringer Ingelheim, BMS, Gilead, GSK, Idenix, Janssen, Merck, Novartis, Presidio, Roche, Santaris, and Vertex. Thomas made no disclosures. Rockstroh reported financial links with Abbott, Boehringer Ingelheim, BMS, Bionor, Gilead, Merck, Janssen, Tibotec, Vertex, GSK, ViiV Healthcare, and Pfizer

Source - http://www.medpagetoday.com/MeetingCoverage/CROI/37678

ABT-450/r plus ABT-072 - Two Oral Drugs Clear HCV Without Interferon

From Medscape Medical News

Two Oral Drugs Clear HCV Without Interferon

 Daniel M. Keller, PhD

May 2, 2012 (Barcelona, Spain) — Twelve weeks of treatment with a combination of 2 direct-acting antiviral drugs plus ribavirin achieved a sustained virologic response rate of more than 80% in patients chronically infected with genotype 1 hepatitis C virus (HCV), Eric Lawitz, MD, from Alamo Medical Research in San Antonio, Texas, reported here at the International Liver Congress 2012.

In a pilot study of 11 treatment-naive noncirrhotic patients, 91% achieved a sustained virologic response at 12 weeks after the end of treatment (SVR12), and 82% had a sustained virologic response at 36 weeks (SVR36).

Currently, the only approved regimens for the treatment of patients with genotype 1 HCV contain interferon. For patients who cannot tolerate interferon, there are no other options.

The 2 direct-acting antiviral drugs are ABT-450, a potent inhibitor of the HCV NS3 protease, and ABT-072 (Abbott Labs), a nonnucleoside inhibitor of HCV NS5B RNA polymerase. Both drugs are dosed orally once daily. ABT-450 is boosted with ritonavir (ABT-450/r) to maintain high ABT-450 exposure and to allow once-daily dosing.

This trial is the first to evaluate the 2 drugs plus ribavirin in an interferon-free regimen for the treatment of HCV genotype 1. The researchers enrolled only patients who were of the interleukin-28B CC genotype, which is the genotype most amenable to treatment with pegylated interferon and ribavirin, in case the trial regimen failed.

Patients were treated with ABT-450/r plus ABT-072 daily plus ribavirin for 12weeks and then followed for 48 weeks after the end of treatment. To be eligible for the study, patients had to be 18 to 65 years of age; had to have HCV genotype 1 infection for at least 6 months, no evidence of cirrhosis or bridging fibrosis, and no coinfection with hepatitis B or HIV; and had to be eligible for treatment with pegylated interferon plus ribavirin.

Baseline characteristics were similar in the the 2 groups (mean age, 56.4 years; mean weight, 79.6 kg). Mean HCV RNA level was 6.93 ± 0.22 log10 IU/mL, and all patients had HCV RNA levels above 800,000 IU/mL.

Rapid, Sustained Virologic Responses

All 11 patients achieved a rapid virologic response and an extended rapid virologic response. Sustained virologic responses at 12, 24, and 36 weeks occurred in 91%, 91%, and 82% of the cohort,respectively.

There were no virologic breakthroughs on therapy, but 2 patients relapsed after therapy ended — one at week 12 and the other at week 36.

All patients experienced adverse effects, but most were mild and included headache, nausea, fatigue, dry skin, and rash. One person had a fasting glucose level above 250 mg/dL, and 2 had indirect bilirubin elevations without concomitant transaminase elevations 1 week after treatment initiation, which resolved with continued dosing. The elevation was consistent with the known effect of ABT-450 on the OATP1B1 bilirubin transporter.

The were no study drug interruptions or discontinuations and no early trial discontinuations. There were also no deaths or serious adverse effects.

Session moderator George Papatheodoridis, MD, associate professor of medicine and gastroenterology at the Medical School of Athens University, staff member at Hippokration General Hospital in Athens, Greece, and member of the European Association for the Study of the Liver Governing Board Scientific Committee, told Medscape Medical News that in light of the small sample size, the 1 late relapse at 36 weeks may or may not be important.

"If these very late relapsers are just 1% or 2%, then it will be of no clinical relevance.... If it's really 1 of 11 (so close to 10%), these late relapsers will be very important," he said. "Because these are new regimens, we don't know how the responders will behave in the long term, so I think the SVR12 should be the gold standard for reporting the results of the trials. [In addition], all trials should still have at least 1 HCV RNA follow-up...1 year after these SVR12 determinations."

Dr. Lawitz reports financial relationships with Abbott, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer  Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, GlobeImmune, Idenix Pharmaceuticals, Idera Pharmaceuticals, Inhibitex Pharmaceuticals, Medarex, Medtronic, Merck, Novartis, Pharmasset, Roche, sanofi-aventis, Schering-Plough, Santaris Pharmaceuticals, Scynexis Pharmaceuticals, Tibotec, Vertex Pharmaceuticals, ViroChem Pharma, and ZymoGenetics. Dr. Papatheodoridis has disclosed no relevant financial relationships.

The International Liver Congress 2012: Abstract 13. Presented April 19, 2012.

EASL-Oral HCV Combo Effective for Genotype One

Oral HCV Combo Effective for Genotype One

By Michael Smith, North American Correspondent, MedPage Today
Published: April 20, 2012

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania.

An all-oral treatment regimen for hepatitis C had high response rates among patients with a hard-to-treat type of virus, a researcher reported.

After 12 weeks of therapy with two investigational direct-acting agents and ribavirin, 91% of patients with genotype one virus went on to have a sustained virologic response (SVR) 24 weeks later, according to Eric Lawitz, MD, of Alamo Medical Research in San Antonio.

It's the first time such a regimen -- given without interferon-alfa -- has shown such high response rates among patients with that type of HCV, Lawitz said at the meeting of the European Association for the Study of the Liver in Barcelona.

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.
•In this small study, a combination oral therapeutic regimen, without interferon-alfa, including a investigational protease inhibitor and an investigational polymerase inhibitor was well tolerated and very effective in treatment of naive noncirrhotic patients with genotype 1 HCV.

The regimen included one standard drug, ribavirin, as well as ABT-450/r, which is given with ritonavir (Norvir) and inhibits the viral NS3 protease inhibitor, and ABT-072, a non-nucleoside NS5B polymerase inhibitor.

In a small study of 11 patients who had not previously been treated for the virus, all showed sharp declines in hepatitis C RNA within three weeks of starting the 12 weeks of therapy and all had undetectable virus from week five through the end of treatment.

One patient relapsed by week eight after the end of treatment, but 91% were still virus-free at week 24 post-therapy and 82% were still clear by 36 weeks, Lawitz said.

He did, however, flag one case of a patient relapsing after the 36-week mark -- a case that has raised eyebrows at the meeting.

Lawitz said the drug's makers are not worried that the case will affect development of the drug, other experts said it may raise a red flag about approvals based on relatively short follow-up times.
"I suspect there are, or will be, others," according to Paul Pockros, MD, of the Scripps Clinic in La Jolla, Calif., who was not part of the study. "If it is one-off, the FDA will say it's fine, but if there are more, it could negatively affect" approvals for all of the new direct-acting agents, Pockros told a reporter.

Until recently, drug studies in hepatitis C used relatively long follow-ups, but in 2011, the FDA said future trials could use SVR 12 weeks after the end of therapy as an endpoint, because relapse usually occurs within that time.

Among the 10 patients with 48-week data available, there have been no more relapses, Lawitz reported.

The drug combination was well-tolerated. Most reported adverse events were mild and the most common were headache, fatigue, nausea, and dry skin. No patient stopped therapy because of adverse events.

There were two cases of transient bilirubin elevation, which took place during the first week of therapy but returned to normal with continued treatment.

The study was sponsored by Abbott Laboratories.
Several authors are employees of the company, which took part in data interpretation and approval of the presentation.

Primary source: EASL

Source reference:
Lawitz E, et al "A 12-week interferon-free regimen of ABT-450/r, ABT-072, and ribavirin was well tolerated and achieved sustained virologic response in 91% treatment-naïve HCV IL28B-CC genotype-1-infected subject" EASL 2012.

EASL:Abbott to Present Positive Phase 2 Results from Multiple Interferon-Free Studies of Combination Regimens for the Treatment of Hepatitis C

April 4
EASL ABSTRACTS NOW READY TO VIEW
Click Here
.
Public
The abstracts will be available on the EASL website, http://www.easl.eu as of today.
..
Abbott to Present Positive Phase 2 Results from Multiple Interferon-Free Studies of Combination Regimens for the Treatment of Hepatitis C

April 04, 2012

Abbott Park, Illinois (NYSE: ABT) — Abbott will present clinical trial results from two different interferon-free, Phase 2 studies for the treatment of hepatitis C (HCV) at the International Liver Congress™ 2012 (ILC 2012), the annual meeting of the European Association for the Study of the Liver (EASL), April 18-22 in Barcelona, Spain. Abstracts for the meeting were published online today.

In the study known as "Co-Pilot," different doses of ABT-450/r, plus ABT-333 and ribavirin administered for 12 weeks showed sustained virological response at 12 weeks post treatment (SVR₁₂) in 95 percent and 93 percent of treatment-naïve genotype 1 (GT1) patients. In these patients, response was independent of HCV subtype, host IL28B genotype or dose of ABT-450/r. In addition, SVR₁₂ was achieved in 47 percent of patients who were previous non-responders to past HCV treatment.

In a separate study, known as "Pilot," 91 percent of genotype 1 infected, treatment-naïve patients taking ABT-450/r and ABT-072 combined with ribavirin administered for 12 weeks, achieved sustained viral response at 24 weeks (SVR₂₄).

Full results with longer-term follow-up data from both studies will be presented at the meeting. Abstracts are available at www.easl.eu.

"We are extremely encouraged to see this level of sustained response with only 12 weeks of therapy in patients who were new to treatment, and to see a response in patients who had failed past treatment because options to cure this population are limited," said Fred Poordad, M.D., chief of hepatology at Cedars-Sinai Medical Center in Los Angeles, and the lead investigator for Co-Pilot and an investigator for Pilot. "These data suggest that an interferon-free, all-oral regimen of direct-acting antiviral medications could be an important new treatment option for HCV, and we look forward to presenting additional data at the meeting."

"At this meeting, Abbott will present some of the first sustained viral response data for short course, interferon-free regimens for the treatment of HCV. The data suggest that with a 12-week regimen containing just two of our direct-acting antiviral medicines, and no peginterferon, we can achieve high cure rates in treatment-naïve, genotype 1 patients," said Scott Brun, M.D., divisional vice president, Infectious Disease Development, Abbott. "Abbott's HCV pipeline includes several compounds in different drug classes and we have the flexibility to study a variety of multi-drug regimens for HCV, with a focus on interferon-free treatments. Abbott is committed to exploring a wide variety of options in our portfolio with the goal of developing optimized regimens to help patients."

Current treatments for HCV remain interferon-based and a significant number of HCV patients are unable or unwilling to take interferon due to contraindications and/or side effects. Specifically targeted antiviral therapies for HCV, such as protease inhibitors and non-nucleoside polymerase inhibitors, may have the potential to increase the proportion of patients in whom the virus can be eradicated.

These two studies represent an important part of Abbott’s broader HCV development program. Larger Phase 2 clinical trials are ongoing, and Abbott expects to present additional data later this year. In addition to its partnership with Enanta Pharmaceuticals on ABT-450 and protease inhibitors, Abbott has internal programs focused on additional viral targets. Abbott currently has investigational medicines with three different mechanisms of action in its ongoing clinical trials, including protease, polymerase and NS5A inhibitors. Abbott is well-positioned to explore combinations of these compounds, a strategy with the potential to markedly transform current treatment practices by shortening therapy duration, improving tolerability and increasing cure rates.

Study M12-746 (Co-Pilot)

Fred Poordad, et al.; Saturday, April 21, 15:30-17:30 CET / 8:30-10:30 a.m. CDT.

"12-Week Interferon-Free Regimen of ABT-450/r+ABT-333+Ribavirin Achieved SVR₁₂ in More Than 90% of Treatment-Naïve HCV Genotype-1-Infected Subjects and 47% of Previous Non-Responders"

• The objectives of this Phase 2 study were to assess safety and tolerability of 12-week, interferon-free regimens in HCV GT1 patients who were either treatment-naïve or previous non-responders. The trial had three arms with three primary endpoints – rapid virological response (RVR) at week 4 and SVR at weeks 4 and 12.
• Enrollment was open to GT1-infected patients regardless of IL28B host genotype and ribavirin dosing was weight-based.
• 95 percent (18 of 19) of treatment-naïve patients infected with HCV GT1
  (17 GT 1a, 2 GT 1b) achieved SVR₁₂ with ABT-450/r 250/100 mg dosed once daily (QD) + ABT-333 400 mg dosed twice daily (BID) + ribavirin (Arm 1).
• 93 percent (13 of 14) of treatment-naïve patients infected with HCV GT1
  (11 GT 1a, 3 GT 1b) achieved SVR₁₂ with ABT-450/r 150/100 mg QD + ABT-333 400 mg BID + ribavirin (Arm 2).
• One patient in Arm 1 discontinued due to asymptomatic isolated ALT/AST elevations at week 2. One patient in Arm 2 discontinued due to noncompliance in week 1. All remaining patients in Arms 1 and 2 completed treatment and achieved SVR₁₂. In Arm 3, six patients experienced viral breakthrough while on treatment and three patients relapsed after treatment stopped.
• In the trial the most common adverse events were fatigue (42 percent), nausea (22 percent) and headache (20 percent).
• 47 percent (8 of 17) of patients with HCV GT1 (16 GT 1a, 1 GT 1b) who had previously not responded to other HCV treatments achieved SVR₁₂ with
  ABT-450/r 150/100 mg QD + ABT-333 400 mg BID + ribavirin (Arm 3).

Study M12-267 (Pilot)

Eric Lawitz et al.; Thursday, April 19, 16:00-18:00 CET / 9:00-11:00 a.m. CDT.

"A 12-Week Interferon-Free Regimen of ABT-450/r, ABT-072, and Ribavirin was Well Tolerated and Achieved Sustained Virologic Response in 91% Treatment-Naïve HCV IL28B-CC Genotype-1-Infected Subjects"

• The objectives of the 12-week, Phase 2 study were to assess the safety, tolerability, pharmacokinetics and antiviral activity of ABT-450/r 150/100 mg QD and ABT-072 400 mg QD + ribavirin administered for 12 weeks.
• The study was conducted in 11 treatment-naïve adults with host IL28B "CC" genotype from multiple ethnic backgrounds with non-cirrhotic HCV GT1
  (8 GT 1a, 3 GT 1b). Ribavirin 1,000-1,200 mg/day was weight-based and dosed twice daily.
• The primary endpoint was percentage of patients with HCV RNA <25 IU/mL from week 4 through 12. Other trial endpoints include early virologic response, RVR and SVR through 24 weeks.
• 100 percent of patients maintained HCV RNA levels <25 IU/mL from weeks
  4 through 12 of treatment, and all had undetectable HCV RNA from week 5 to the end of treatment.
• 91 percent of patients (10 of 11) achieved SVR_24.
• In the trial, the most common adverse events reported were headache, fatigue, nausea and dry skin. There were no premature discontinuations.

ABT-450 is being developed with low dose ritonavir (ABT-450/r), which enhances the pharmacokinetic properties of ABT-450. The use of ritonavir 100 mg with ABT-450 for the treatment of HCV is investigational

In addition to the oral presentations, Abbott has six poster presentations at ILC 2012:
.

• Tami Pilot-Matias et al.; Friday, April 20 (11:00-11:30, 12:30-14:00, 15:30-16:00 CET)
  "In vitro combinatory effect of HCV NS3/4A protease inhibitor ABT-450, NS5A inhibitor ABT-267, and non-nucleoside NS5B polymerase inhibitor ABT-333"
• Robert W. Baran et al.; Friday, April 20 (11:00-11:30, 12:30-14:00, 15:30-16:00 CET)
  "Hepatitis C Virus Patient Reported Outcomes (HCVPRO): Development and Validation of a Disease-Specific Patient Reported Outcomes Instrument for Health-Related Quality of Life Measurement"
• Eric Lawitz et al.; Saturday, April 21 (11:00-11:30, 12:30-13:30, 15:00-15:30 CET)
  "Safety and antiviral activity of ABT-267, a novel NS5A inhibitor, during 3-day monotherapy: first study in HCV genotype-1 (GT1)-infected treatment-naïve subjects"

• J Greg Sullivan et al.; Saturday, April 21 (11:00-11:30, 12:30-13:30, 15:00-15:30 CET)
  "ABT-267 combined with pegylated interferon alpha-2a/ribavirin in genotype 1 (GT1) HCV-infected treatment-naïve subjects: 12 week antiviral and safety analysis"
• Eric Lawitz et al; Saturday, April 21 (11:00-11:30, 12:30-13:30, 15:00-15:30 CET)
  "ABT-450/ritonavir (ABT-450/r) combined with pegylated interferon alpha-2a/ribavirin after 3-day monotherapy in genotype 1 (GT1) HCV-infected treatment-naïve subjects: 12-week sustained virologic response (SVR₁₂) and safety results"
• Fred Poordad et al.; Saturday, April 21 (11:00-11:30, 12:30-13:30, 15:00-15:30 CET)
  "ABT-072 or ABT-333 combined with pegylated interferon/ribavirin after 3-day monotherapy in HCV genotype 1 (GT1)-infected treatment-naïve subjects: 12-week sustained virologic response (SVR₁₂) and safety results"

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.

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 aviumcomplex (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.

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