2012 pipeline report launched in Washington: HIV, HCV, TB, PEP, cure and vaccine research.
On July 21- 2012 HIV i-Base (U.K.) and Treatment Action Group (TAG) (U.S.) released their new comprehensive "2012 Pipeline Report"
The report is ready to view at the new website launched today by "TAG"
For the HCV community, there is a particular article in the report written by Tracy Swan and Karyn Kaplan you won't want to miss;
Hepatitis C Drug Development Goes from Pony Ride to Rocket Launch.
The in depth report includes some of the following topics; HCV drug resistance, DAA drug-drug interactions, nucleosides and nucleotide polymerase inhibitors, HCV protease inhibitors, the next generation of drugs, HCV quad therapy, SVR-4 ,SVR-12, interferon free therapy, ABT-450/r, ACH-1625, BI 201335, bms-650032, bms-790052, Danoprevir, genotypes 1-4, GS-7977 Formally/PSI-7977, GS-9256, Lambda, MK-7009, TMC435 and much more....
The 2012 Pipeline Report: HIV, Hepatitis C Virus (HCV), and Tuberculosis (TB) Drugs, Diagnostics, Vaccines, and Preventive Technologies in Development by Polly Clayden, Simon Collins, Colleen Daniels, Nathan Geffen, Mark Harrington, Richard Jefferys, Coco Jervis, Karyn Kaplan, Erica Lessem, and Tracy Swan is available online at:
http://www.treatmentactiongroup.org/pipeline-report/2012
and as an interactive web report at:
http://www.pipelinereport.org.
Showing posts with label TMC435. Show all posts
Showing posts with label TMC435. Show all posts
Friday, July 13, 2012
Tuesday, April 24, 2012
New Protease Inhibitor TMC435 Cures Most HCV Patients
From Medscape Medical News
New Protease Inhibitor TMC435 Cures Most HCV Patients
Daniel M. Keller, PhD
April 24, 2012 (Barcelona, Spain) — In patients infected with hepatitis C virus (HCV) genotype 1 for whom previous treatment with pegylated interferon plus ribavirin (PR) failed to eliminate the virus, treatment with TMC435 plus PR was significantly more effective than PR plus placebo. TMC435 is a once-daily oral therapy that inhibits HCV NS3/4A protease.
Stefan Zeuzem, MD, professor of medicine and chief of the Department of Medicine I at the J.W. Goethe University Hospital in Frankfurt, Germany, presented the results of the international, double-blind, placebo-controlled phase 2b ASPIRE clinical trial here at The International Liver Congress 2012.
The 462 patients in this trial were assigned to 48 weeks of active therapy with 1 of 4 treatment regimens: TMC435 + PR for 12 weeks, followed by PR + placebo weeks for 36 weeks; TMC435 + PR for 24 weeks, followed by PR + placebo for 24 weeks; TMC435 + PR for 48 weeks; or PR + placebo for 48 weeks (control group).
In patients receiving TMC435, the dose was 100 or 150 mg daily. All patients were followed for 24 weeks after the 48-week treatment period.
Eligible men and women were 18 to 70 years of age, had a body weight of 40 to 125 kg, were chronically infected with HCV genotype 1 HCV, and had plasma HCV RNA greater than 10,000 IU/mL. They had to have received at least 1 previous course of PR for at least 12 consecutive weeks.
Patients were ineligible for the trial if they had decompensated liver disease or liver disease from any cause other than HCV; if they had hepatocellular carcinoma; if they were infected with HIV, hepatitis B virus, or any HCV that was not genotype 1; or if they had any laboratory or hematologic abnormalities.
At baseline, about two thirds of the patients were men, median age was about 50 years, body weight ranged from 80.0 to 84.8 kg, and 83% to 89% had HCV RNA greater than 800,000 IU/mL. Previously in each group, about 40% had relapsed, 35% had partially responded, and 25% had not responded.
In the 3 TMC435 groups (both the 100 and 150 mg doses), 53% to 68% of patients achieved rapid viral responses, compared with 2% in the control group (P < .001 for all groups vs control group). Rapid viral response meant there was undetectable virus in the blood at week 4.
The sustained viral response rates at 24 weeks (SVR24) ranged from 61% to 80% for the TMC435 groups, compared with 23% in the control group.
In the TMC435 groups, compared with the control group, previous responders had the highest SVR24 rates (85% vs 37%), followed by previous partial responders (57% to 75% vs 9%), followed by previous nonresponders (46% to 51% vs 19%).
No patients with advanced liver fibrosis achieved a virologic cure in the control group, whereas with TMC435, "there was a substantial chance for the patients to achieve sustained virologic response rates," Dr. Zeuzem reported.
TMC435 Well Tolerated
Discontinuation of treatment because of viral breakthrough was 9% to 17% in the TMC435 groups and 53% in the control group. Viral relapse occurred in 6% to 18% of the TMC435 group and 44% of the control group.
The incidence and severity of adverse events were similar in the TMC435 and control groups. Serious adverse events affected 6% to 10% of patients in the TMC435 groups and 6% in the control group. Grade 3/4 adverse events occurred in 28% to 36% of the TMC435 groups and in 26% of the control group. The most frequently reported adverse events in patients receiving TMC435 were headache, fatigue, and influenza-like illness, but these events were present at equivalent levels in the control group.
However, pruritus was more common in the TMC435 groups than in the control group (35% VS17%). Similarly, more rash of any type occurred in the TMC435 groups than in the control group (23% to 30% vs 18%). However, less than 1% of patients receiving TMC435 experienced rash of grade 3 or lower.
The incidence of adverse events leading to treatment discontinuation and serious adverse events was similar in all groups. Decreases in and recovery of hemoglobin values and neutrophil counts were equivalent in all groups. However, the TMC435 groups showed mild and reversible increases in bilirubin not accompanied by changes in any other liver parameters.
For patients receiving 150 mg of TMC435, 85% of previous relapsers achieved SVR24, 75% of previous partial responders achieved SVR24, 51% of previous nonresponders achieved SVR24, and 31% to 82% of patients with cirrhosis achieved SVR24.
Dr. Zeuzem and colleagues conclude that in patients with HCV genotype 1 who failed previous PR therapy, once-daily TMC435 plus PR was significantly more effective in producing a sustained viral response than PR plus placebo.
In comparing the different durations of administration of TMC435, Dr. Zeuzem explained that "TMC435 for 12 weeks in combination with pegylated interferon and ribavirin for 48 weeks achieves optimal biologic response rates." Longer treatment with TMC435 did not produce any better virologic responses.
The drug is now entering phase 3 trials for both treatment-naive and treatment-experienced patients.
Session moderator Mark Thursz, MBBS, MD, secretary general of the European Association for the Study of the Liver and professor of hepatology in the Department of Medicine at Imperial College, London, United Kingdom, asked Dr. Zeuzem if hepatologists need to continue to use SVR24 as the end point of a trial or if the follow-up period can be shortened by using sustained viral response at 12 weeks (SVR12) as the end point.
Dr. Zeuzem explained that current trials "typically use an SVR at week 12 of the follow-up period, and the concordance rates are extremely high [with SVR24]; therefore, SVR12 is the new standard."
He does not think there is a major difference between SVR12 and SVR24 for treatment-naive patients, nonresponders, or relapsers with an interferon-containing protocol such as this one. "I'm a little bit more conservative in trials using completely new drugs, [such as]...interferon-free regimens and all-oral regimens," Dr. Zeuzem said. He would like to see trials demonstrating the equivalence of SVR12 and SVR24 in those cases before adopting SVR12 for those drug regimens.
Dr. Thursz told Medscape Medical News that he, too, believes that SVR12 will be the new end point and will replace SVR24 as new drugs enter trials. "The only proviso is for people who've previously been treated and have been classified as null responders — that's a group of people with hepatitis C [in whom] the virus has not dropped by 2 logs [after 12 weeks of treatment]," he said. "These people are going to be really difficult to treat and very resistant to pretty much any kind of medication. I have some reservation about that group; otherwise, SVR12 is undoubtedly going to be, as it were, the standard."
Another group of particular concern is patients with advanced fibrosis or cirrhosis. "We know, certainly with interferon-based therapies, that response rates are much lower in that group. Then there is some concern in cirrhotics, particularly cirrhotics who've decompensated, that the metabolism of the drugs is going to be slightly different and may cause some problems," Dr. Thursz cautioned.
Dr. Zeuzem reports being a consultant for Abbott, Achillion, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead, Idenix, Inhibitex, iTherX, Janssen, Merck, Novartis, Presidio Pharmaceuticals, Roche, Santaris, and Vertx Pharmaceuticals. Dr. Thursz has disclosed no relevant financial relationships.
The International Liver Congress 2012: Abstract 2. Presented April 19, 2012.
New Protease Inhibitor TMC435 Cures Most HCV Patients
Daniel M. Keller, PhD
April 24, 2012 (Barcelona, Spain) — In patients infected with hepatitis C virus (HCV) genotype 1 for whom previous treatment with pegylated interferon plus ribavirin (PR) failed to eliminate the virus, treatment with TMC435 plus PR was significantly more effective than PR plus placebo. TMC435 is a once-daily oral therapy that inhibits HCV NS3/4A protease.
Stefan Zeuzem, MD, professor of medicine and chief of the Department of Medicine I at the J.W. Goethe University Hospital in Frankfurt, Germany, presented the results of the international, double-blind, placebo-controlled phase 2b ASPIRE clinical trial here at The International Liver Congress 2012.
The 462 patients in this trial were assigned to 48 weeks of active therapy with 1 of 4 treatment regimens: TMC435 + PR for 12 weeks, followed by PR + placebo weeks for 36 weeks; TMC435 + PR for 24 weeks, followed by PR + placebo for 24 weeks; TMC435 + PR for 48 weeks; or PR + placebo for 48 weeks (control group).
In patients receiving TMC435, the dose was 100 or 150 mg daily. All patients were followed for 24 weeks after the 48-week treatment period.
Eligible men and women were 18 to 70 years of age, had a body weight of 40 to 125 kg, were chronically infected with HCV genotype 1 HCV, and had plasma HCV RNA greater than 10,000 IU/mL. They had to have received at least 1 previous course of PR for at least 12 consecutive weeks.
Patients were ineligible for the trial if they had decompensated liver disease or liver disease from any cause other than HCV; if they had hepatocellular carcinoma; if they were infected with HIV, hepatitis B virus, or any HCV that was not genotype 1; or if they had any laboratory or hematologic abnormalities.
At baseline, about two thirds of the patients were men, median age was about 50 years, body weight ranged from 80.0 to 84.8 kg, and 83% to 89% had HCV RNA greater than 800,000 IU/mL. Previously in each group, about 40% had relapsed, 35% had partially responded, and 25% had not responded.
In the 3 TMC435 groups (both the 100 and 150 mg doses), 53% to 68% of patients achieved rapid viral responses, compared with 2% in the control group (P < .001 for all groups vs control group). Rapid viral response meant there was undetectable virus in the blood at week 4.
The sustained viral response rates at 24 weeks (SVR24) ranged from 61% to 80% for the TMC435 groups, compared with 23% in the control group.
In the TMC435 groups, compared with the control group, previous responders had the highest SVR24 rates (85% vs 37%), followed by previous partial responders (57% to 75% vs 9%), followed by previous nonresponders (46% to 51% vs 19%).
No patients with advanced liver fibrosis achieved a virologic cure in the control group, whereas with TMC435, "there was a substantial chance for the patients to achieve sustained virologic response rates," Dr. Zeuzem reported.
TMC435 Well Tolerated
Discontinuation of treatment because of viral breakthrough was 9% to 17% in the TMC435 groups and 53% in the control group. Viral relapse occurred in 6% to 18% of the TMC435 group and 44% of the control group.
The incidence and severity of adverse events were similar in the TMC435 and control groups. Serious adverse events affected 6% to 10% of patients in the TMC435 groups and 6% in the control group. Grade 3/4 adverse events occurred in 28% to 36% of the TMC435 groups and in 26% of the control group. The most frequently reported adverse events in patients receiving TMC435 were headache, fatigue, and influenza-like illness, but these events were present at equivalent levels in the control group.
However, pruritus was more common in the TMC435 groups than in the control group (35% VS17%). Similarly, more rash of any type occurred in the TMC435 groups than in the control group (23% to 30% vs 18%). However, less than 1% of patients receiving TMC435 experienced rash of grade 3 or lower.
The incidence of adverse events leading to treatment discontinuation and serious adverse events was similar in all groups. Decreases in and recovery of hemoglobin values and neutrophil counts were equivalent in all groups. However, the TMC435 groups showed mild and reversible increases in bilirubin not accompanied by changes in any other liver parameters.
For patients receiving 150 mg of TMC435, 85% of previous relapsers achieved SVR24, 75% of previous partial responders achieved SVR24, 51% of previous nonresponders achieved SVR24, and 31% to 82% of patients with cirrhosis achieved SVR24.
Dr. Zeuzem and colleagues conclude that in patients with HCV genotype 1 who failed previous PR therapy, once-daily TMC435 plus PR was significantly more effective in producing a sustained viral response than PR plus placebo.
In comparing the different durations of administration of TMC435, Dr. Zeuzem explained that "TMC435 for 12 weeks in combination with pegylated interferon and ribavirin for 48 weeks achieves optimal biologic response rates." Longer treatment with TMC435 did not produce any better virologic responses.
The drug is now entering phase 3 trials for both treatment-naive and treatment-experienced patients.
Session moderator Mark Thursz, MBBS, MD, secretary general of the European Association for the Study of the Liver and professor of hepatology in the Department of Medicine at Imperial College, London, United Kingdom, asked Dr. Zeuzem if hepatologists need to continue to use SVR24 as the end point of a trial or if the follow-up period can be shortened by using sustained viral response at 12 weeks (SVR12) as the end point.
Dr. Zeuzem explained that current trials "typically use an SVR at week 12 of the follow-up period, and the concordance rates are extremely high [with SVR24]; therefore, SVR12 is the new standard."
He does not think there is a major difference between SVR12 and SVR24 for treatment-naive patients, nonresponders, or relapsers with an interferon-containing protocol such as this one. "I'm a little bit more conservative in trials using completely new drugs, [such as]...interferon-free regimens and all-oral regimens," Dr. Zeuzem said. He would like to see trials demonstrating the equivalence of SVR12 and SVR24 in those cases before adopting SVR12 for those drug regimens.
Dr. Thursz told Medscape Medical News that he, too, believes that SVR12 will be the new end point and will replace SVR24 as new drugs enter trials. "The only proviso is for people who've previously been treated and have been classified as null responders — that's a group of people with hepatitis C [in whom] the virus has not dropped by 2 logs [after 12 weeks of treatment]," he said. "These people are going to be really difficult to treat and very resistant to pretty much any kind of medication. I have some reservation about that group; otherwise, SVR12 is undoubtedly going to be, as it were, the standard."
Another group of particular concern is patients with advanced fibrosis or cirrhosis. "We know, certainly with interferon-based therapies, that response rates are much lower in that group. Then there is some concern in cirrhotics, particularly cirrhotics who've decompensated, that the metabolism of the drugs is going to be slightly different and may cause some problems," Dr. Thursz cautioned.
Dr. Zeuzem reports being a consultant for Abbott, Achillion, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead, Idenix, Inhibitex, iTherX, Janssen, Merck, Novartis, Presidio Pharmaceuticals, Roche, Santaris, and Vertx Pharmaceuticals. Dr. Thursz has disclosed no relevant financial relationships.
The International Liver Congress 2012: Abstract 2. Presented April 19, 2012.
Thursday, April 19, 2012
EASL-TMC435 Demonstrates Statistically Higher Viral Cure Rates (SVR24) Compared to Placebo in HCV Patients Who Had Failed Prior Treatment
Once-daily TMC435 Demonstrates Statistically Higher Viral Cure Rates (SVR24) Compared to Placebo in HCV Patients Who Had Failed Prior Treatment
-- Janssen R&D Presents Final Safety and Efficacy Results from Phase 2b ASPIRE Study of Once-daily TMC435 at EASL --
BARCELONA, Spain, April 19, 2012 /PRNewswire/ -- Janssen R&D Ireland today will present final results from ASPIRE, a phase 2b study of TMC435, a once daily investigational hepatitis C virus (HCV) NS3/4A protease inhibitor. Results show that the medication was effective and well-tolerated when given in combination with pegylated-interferon and ribavirin (PegIFN/RBV) in the treatment of chronically-infected genotype 1 HCV patients who had failed previous treatment. The data are featured in an oral presentation at the 47th Annual Meeting of the European Association for the Study of the Liver (EASL) in Barcelona, Spain, April 18-22, 2012.
Results from the final ASPIRE analysis show that TMC435 administered in combination with PegIFN/RBV resulted in significantly higher sustained virologic response (SVR24) rates compared to placebo plus PegIFN/RBV. The ASPIRE study evaluated chronically-infected genotype 1 HCV patients who had relapsed, showed partial response, or no response after a prior course of PegIFN/RBV. In the TMC435 arms, 53 to 68 percent of patients achieved rapid virologic response [RVR; HCV RNA<25 (undetectable)], compared to 2 percent of the placebo group. For patients in the TMC435 treatment groups dosed with TMC435 100 mg and 150mg, 61-70 percent of patients and 67-80 percent of patients achieved SVR24, respectively, compared to 23 percent of patients achieving SVR24 in the placebo arm. For null-responders to prior HCV therapy dosed with TMC435 150 mg, 51 percent of patients in the TMC435 treatment groups achieved SVR24, compared to 19 percent in placebo group. When treated with TMC435 150 mg, 75 percent of prior partial responders and 85 percent of patients who previously relapsed reached SVR24, versus 9 and 37 percent taking placebo, respectively. Once-daily TMC435 was well tolerated in this population with comparable incidence of adverse events between TMC435 and placebo groups except for influenza-like illness, pruritus, and rash (any type). Results showed comparable on treatment changes in hemoglobin levels and neutrophil counts between groups and mild, isolated and reversible increases in bilirubin amongst TMC435 treated subjects.
TMC435 150 mg administered once daily (q.d.) is being investigated in phase 3 trials in various patient populations. Two global randomized trials investigate adults with chronic genotype 1 hepatitis C infection – QUEST-1 (TMC435-C208) and QUEST-2 (TMC435-C216) compare TMC435 in combination with PegIFN/RBV against a placebo among treatment-naive adults, and PROMISE (TMC435-C3007) compares TMC435 combined with PegIFN/RBV versus PegIFN/RBV alone in patients who have experienced a viral relapse following previous interferon-based treatment. The recently-launched global phase 3 study HPC3001 assesses TMC435 versus telaprevir, both in combination with PegIFN/RBV, in treatment-experienced patients. Additionally, the global phase 3 trial HPC3011 tests the safety and efficacy of TMC435 in treatment-naive or treatment-experienced HCV genotype 4 infected patients. The phase 3 program in Japan evaluates the efficacy and safety of TMC435 in treatment-naive, relapsed patients, partial and null responders.
"Chronic hepatitis C is a devastating disease for millions of patients infected worldwide and while considered curable, some patient populations remain almost unresponsive to current antiviral therapy, including those with advanced cirrhosis," said Stefan Zeuzem, M.D., lead clinical investigator and Professor of Medicine and Chief of the Department of Medicine, at the Goethe University Hospital, Frankfurt, Germany. "We are encouraged by the results of once-daily TMC435 in combination with peginterferon alfa and ribavirin in achieving significantly higher sustained virologic response rates compared with peginterferon alfa and ribavirin alone in patients who have not had success with previous antiviral treatments. This analysis reinforces the superior viral cure rates to placebo and promising safety profile seen in the phase 2b PILLAR study in treatment-naive patients."
TMC435 is being developed by Janssen Research & Development in partnership with Medivir.
"Janssen is pleased to present the final analysis of the phase 2b ASPIRE study at EASL. The continued development of TMC435, which is currently being investigated in registrational phase 3 studies in both treatment-naive and treatment-experienced patients, reinforces our strong commitment to the development of new therapies that will improve the lives of those impacted by HCV, including patients whose disease is particularly difficult to treat," said Maria Beumont, M.D., Global Medical Leader TMC435 at Janssen.
About the ASPIRE Study
The ASPIRE study (TMC435-C206) was a seven-arm, global phase 2b randomized, double-blind, placebo controlled study that evaluated the effect of TMC435 in combination with pegylated-interferon and ribavirin (PegIFN/RBV). The study was comprised of 462 patients infected with genotype-1 hepatitis C virus who had failed prior treatment with PegIFN/RBV, meaning patients that had relapsed, achieved partial response, or achieved no response (null responders) to PegIFN/RBV treatment.
Patients were equally randomized to one of seven different treatment arms, six groups taking TMC435 and one placebo arm. TMC435 was administered once daily at a dose of either 100 mg or 150 mg given for either 12, 24, or 48 weeks in combination with PegIFN/RBV. PegIFN/RBV treatment was continued in the groups that received TMC435 for 12 or 24 weeks. Total treatment duration was 48 weeks in all patients.
For all patients treated in the TMC435 groups dosed with 100 mg and 150 mg, the most common adverse events were headache (31, 40 percent and 36 percent for TMC435 100mg, TMC435 150 mg and placebo, respectively), fatigue (47, 41 and 44 percent, respectively), influenza-like illness (35, 24 and 20 percent, respectively), pruritis (34, 35 and 17 percent) and neutropenia (23, 28 and 17 percent, respectively). Most adverse events were mild to moderate in severity. Adverse events leading to treatment discontinuation of TMC435/placebo were reported in 7 to 9 percent of patients in TMC435 arms and 5 percent in placebo arm.
Other Janssen R&D Presentations at EASL
In conjunction with the final sustained virologic response (SVR24) results from ASPIRE, Janssen R&D is presenting virology analysis data from ASPIRE, a comparison of two quantitative HCV RNA assays and a study evaluating potential photosensitivity associated with TMC435:
- "TMC435 in patients infected with HCV genotype 1 who have failed previous pegylated interferon/ribavirin treatment: virologic analysis of the ASPIRE study." O. Lenz. (Oral)
- "Comparison of two quantitative HCV RNA assays in samples from patients treated with a protease inhibitor-based therapy: implications for response guided therapy." B. Fevery. (Oral)
- "Absence of photosensitivity potential of TMC435 in healthy volunteers." A. Simion. (Poster)
HCV is a blood-borne infectious disease that affects the liver. With an estimated 210 million people infected worldwide and three to four million people newly infected each year, HCV puts a significant burden on patients and society. Chronic infection with HCV can lead to liver cancer and other serious and fatal liver diseases, and is the most common cause of liver transplant worldwide. Pegylated interferon combined with ribavirin can cause serious side effects and only leads to sustained viral clearance in 40 to 50 percent of genotype 1 patients. The development of new therapies, particularly direct antivirals with different modes of action, may allow HCV patients to undergo a shorter and more effective treatment regimen.
About Janssen R&D Ireland
Janssen R&D Ireland, one of the Janssen Pharmaceutical Companies of Johnson & Johnson, is a global pharmaceutical and research development company. The Company's main research and development facilities are in Beerse, Belgium with offices in Titusville, New Jersey and Cork, Ireland. The Company is dedicated to the discovery and development of innovative HIV/AIDS and hepatitis C drugs, and anti-infectives for diseases of high unmet medical need.
Contact:
Media
Hans Vanavermaete: Cell + 32 (478) 44 72 78
Distributed by PR Newswire on behalf of Janssen R&D
Tuesday, March 13, 2012
TMC435-New Studies in Phase III Program
HUDDINGE, Sweden--(BUSINESS WIRE)--Mar 13, 2012 - Regulatory News:
HPC3001
HPC3001 is a phase III efficacy, safety and tolerability study comparing TMC435 versus telaprevir, each in combination with Pegylated Interferon α-2a (PegINF) and ribavirin (RBV), in hepatitis C genotype-1 infected patients who were null or partial responders to prior PegINF/RBV therapy. The study which is a randomized, double-blind, double-dummy, two-arm study is targeted to enroll 744 patients.
The aim of the study is to demonstrate the efficacy of TMC435 based therapy compared to the approved telaprevir regimen in this difficult to treat population.
Patients will receive TMC435 150 mg once daily or telaprevir 750 mg administered every eight hours (q8h) in combination with PegINF/RBV for 12 weeks followed by 36 weeks of PegIFN/RBV alone. The primary endpoint of the study is sustained virological response at 12 weeks (SVR12).
HPC3011
HPC3011 is an open label, single arm phase III trial to explore the efficacy, safety and tolerability of TMC435 150 mg once daily, in combination with PegIFN/RBV in 100 treatment naïve or treatment experienced, Hepatitis C genotype-4 infected patients.
Current standard of care treatment for chronic HCV genotype-4 infection consists of 48 weeks of PegIFN/RBV with a large proportion of patients do not achieve SVR with this treatment regimen.
All subjects will receive 12 weeks triple therapy of TMC435 150 mg once daily and PegIFN/RBV, followed by PegIFN/RBV alone. The duration of total treatment is response guided in treatment naïve and prior relapser subjects and patients are eligible to stop all treatment at week 24 if predefined response-guided criteria are met. Subjects with cirrhosis will receive 48 weeks of therapy, irrespective of on-treatment virologic response and treatment history. The primary endpoint in the study is SVR12.
TMC435 - Ongoing global phase III program in brief:
About TMC435
TMC435 is an investigational HCV protease inhibitor in late phase III clinical development. It is an efficacious, safe and well-tolerated once-daily (q.d.) drug jointly developed by Janssen Pharmaceuticals to treat chronic hepatitis C virus infections.
TMC435 is in phase III clinical development in combination with PegIFN/RBV but is also being evaluated with Direct-acting Antiviral (DAA) agents in interferon-free combinations both with and without ribavirin (RBV).
For additional information please visit www.medivir.com and www.clinicaltrials.gov
About Hepatitis C
Hepatitis C is a blood-borne infectious disease of the liver and is a leading cause of chronic liver disease and liver transplants. The WHO estimates that nearly 180 million people worldwide, or approximately 3% of the world's population, are infected with hepatitis C virus (HCV). The CDC has reported that almost three million people in the United States are chronically infected with HCV.
About Medivir
Medivir is an emerging research-based specialty pharmaceutical company focused on the development of high-value treatments for infectious diseases. Medivir has world class expertise in polymerase and protease drug targets and drug development which has resulted in a strong infectious disease R&D portfolio. The Company's key pipeline asset is TMC435, a novel protease inhibitor in phase III clinical development for hepatitis C that is being developed in collaboration with Janssen Pharmaceuticals.
In June 2011, Medivir acquired the specialty pharmaceutical company BioPhausia to ensure timely commercialisation of TMC435 in the Nordic markets, once approved.
Medivir's first product, the unique cold sore product Xerese®/Xerclear®, was launched on the US market in 2011. Xerese®/Xerclear®, which has been approved in both the US and Europe, is being launched in collaboration with GlaxoSmithKline to be sold OTC in Europe, Japan and Russia. Rights in North America, Canada and Mexico were sold to Meda AB in June 2011. Medivir has retained the Rx rights for Xerclear® in Sweden and Finland.
For more information about Medivir, please visit the Company's website: www.medivir.com
This information was brought to you by Cision http://www.cisionwire.com
Contact: Rein Piir
EVP Corporate Affairs & IR M:Communications
Medivir@mcomgroup.com
Medivir Mobil: +46 708 537 292
or
Europe
Mary-Jane Elliott
Amber Bielecka
Hollie Vile
+44(0)20 7920 2330
- Study in previous non-responder Hepatitis C genotype-1 infected patients
- Study in Hepatitis C genotype-4 infected patients
HPC3001
HPC3001 is a phase III efficacy, safety and tolerability study comparing TMC435 versus telaprevir, each in combination with Pegylated Interferon α-2a (PegINF) and ribavirin (RBV), in hepatitis C genotype-1 infected patients who were null or partial responders to prior PegINF/RBV therapy. The study which is a randomized, double-blind, double-dummy, two-arm study is targeted to enroll 744 patients.
The aim of the study is to demonstrate the efficacy of TMC435 based therapy compared to the approved telaprevir regimen in this difficult to treat population.
Patients will receive TMC435 150 mg once daily or telaprevir 750 mg administered every eight hours (q8h) in combination with PegINF/RBV for 12 weeks followed by 36 weeks of PegIFN/RBV alone. The primary endpoint of the study is sustained virological response at 12 weeks (SVR12).
HPC3011
HPC3011 is an open label, single arm phase III trial to explore the efficacy, safety and tolerability of TMC435 150 mg once daily, in combination with PegIFN/RBV in 100 treatment naïve or treatment experienced, Hepatitis C genotype-4 infected patients.
Current standard of care treatment for chronic HCV genotype-4 infection consists of 48 weeks of PegIFN/RBV with a large proportion of patients do not achieve SVR with this treatment regimen.
All subjects will receive 12 weeks triple therapy of TMC435 150 mg once daily and PegIFN/RBV, followed by PegIFN/RBV alone. The duration of total treatment is response guided in treatment naïve and prior relapser subjects and patients are eligible to stop all treatment at week 24 if predefined response-guided criteria are met. Subjects with cirrhosis will receive 48 weeks of therapy, irrespective of on-treatment virologic response and treatment history. The primary endpoint in the study is SVR12.
TMC435 - Ongoing global phase III program in brief:
- TMC435-C208 or QUEST-1 in 375 treatment-naïve genotype-1 patients
- TMC435-C216 or QUEST-2 in 375 treatment-naïve genotype-1 patients
- TMC435-C3007 or PROMISE in 375 genotype-1 patients who have relapsed after prior interferon-based treatment
- Phase III program in Japan, includes 417 genotype-1 treatment naïve and treatment experienced patients
About TMC435
TMC435 is an investigational HCV protease inhibitor in late phase III clinical development. It is an efficacious, safe and well-tolerated once-daily (q.d.) drug jointly developed by Janssen Pharmaceuticals to treat chronic hepatitis C virus infections.
TMC435 is in phase III clinical development in combination with PegIFN/RBV but is also being evaluated with Direct-acting Antiviral (DAA) agents in interferon-free combinations both with and without ribavirin (RBV).
For additional information please visit www.medivir.com and www.clinicaltrials.gov
About Hepatitis C
Hepatitis C is a blood-borne infectious disease of the liver and is a leading cause of chronic liver disease and liver transplants. The WHO estimates that nearly 180 million people worldwide, or approximately 3% of the world's population, are infected with hepatitis C virus (HCV). The CDC has reported that almost three million people in the United States are chronically infected with HCV.
About Medivir
Medivir is an emerging research-based specialty pharmaceutical company focused on the development of high-value treatments for infectious diseases. Medivir has world class expertise in polymerase and protease drug targets and drug development which has resulted in a strong infectious disease R&D portfolio. The Company's key pipeline asset is TMC435, a novel protease inhibitor in phase III clinical development for hepatitis C that is being developed in collaboration with Janssen Pharmaceuticals.
In June 2011, Medivir acquired the specialty pharmaceutical company BioPhausia to ensure timely commercialisation of TMC435 in the Nordic markets, once approved.
Medivir's first product, the unique cold sore product Xerese®/Xerclear®, was launched on the US market in 2011. Xerese®/Xerclear®, which has been approved in both the US and Europe, is being launched in collaboration with GlaxoSmithKline to be sold OTC in Europe, Japan and Russia. Rights in North America, Canada and Mexico were sold to Meda AB in June 2011. Medivir has retained the Rx rights for Xerclear® in Sweden and Finland.
For more information about Medivir, please visit the Company's website: www.medivir.com
This information was brought to you by Cision http://www.cisionwire.com
Contact: Rein Piir
EVP Corporate Affairs & IR M:Communications
Medivir@mcomgroup.com
Medivir Mobil: +46 708 537 292
or
Europe
Mary-Jane Elliott
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Hollie Vile
+44(0)20 7920 2330
Monday, February 27, 2012
News Ticker:Serum Vitamin D Levels Are Not Predictive of the Progression of Chronic Liver Disease in Hepatitis C Patients with Advanced Fibrosis
New On The Blog
In The News
HepCBC hosts educational forum
New U.S. statistics show that viral hepatitis deaths are surpassing those from HIV – the virus that leads to AIDS.
This stirring news has helped lead HepCBC Hepatitis C Education and Prevention Society to host a forum to discuss new guidelines for the management of hepatitis C and B recommended by liver specialists.
The forum is being held Friday, March 2 from 9 a.m. to 4 p.m. at Royal Jubilee Hospital’s Begbie Hall, 2101 Richmond Ave.
Five Canadian liver specialists will present new recommended guidelines for managing HCV. Each of their presentations will be followed by a public question and answer and comment period. The public is invited, but as seating is limited, online pre-registration is required via www.hepcbc.ca.
Published: Monday, Feb. 27, 2012 - 5:48 am
BEIJING -- China says it is sending medical experts to investigate an outbreak of hepatitis C among more than 200 people in the southern province of Guangdong.
Ministry of Health spokesman Deng Haihua said Monday that mistakes in medical procedures may have caused the infections in the province's Zijin county. Deng said strengthened preventative measures were ordered at clinics and hospitals in the area to prevent the further spread of the virus.
Hepatitis C is spread primarily through blood and can lead to life-threatening liver damage. Infection can occur through blood transfusions, poorly sterilized equipment or the sharing of intravenous drug needles.
Research
Serum Vitamin D Levels Are Not Predictive of the Progression of Chronic Liver Disease in Hepatitis C Patients with Advanced Fibrosis
Source PloS One
Introduction Only
Hepatic fibrosis results from wound healing following acute and chronic liver injury. In response to chronic hepatic inflammation, parenchymal cells release extracellular matrix proteins including type I collagen, resulting in the progressive deposition of, and accumulation of, fibrosis. Ultimately, fibrotic tissue can replace hepatocytes and disrupt lobular architecture, the hallmark of cirrhosis, which, in turn, results eventually in hepatic dysfunction. [1]
Emerging data suggest that vitamin D is an important modulator of both the inflammatory response and wound healing. [2], [3] Vitamin D may modulate the inflammatory response and subsequent fibrosis via inhibition of TNF-α, a cytokine that plays a central role in the regulation of the immune response [4], [5] and by inhibiting the development of fibrosis directly through suppression of TGF-β, a multifunctional cytokine that may influence fibrosis progression [6].[7].[8].
The importance of vitamin D in immune modulation and deposition of fibrosis may extend to the liver, which plays an important role in vitamin D homeostasis. The liver is the site of the conversion of vitamin D3 to 25-hydroxy-vitamin D (25-OH-vitamin D) and may be a site of vitamin D storage. [9] In addition, vitamin D receptors exist on hepatocytes and other hepatic parenchymal cells, including hepatic stellate cells. As in the kidney, vitamin D is postulated to play an antiinflammatory and antifibrotic role in the liver via binding to promoters of target genes, leading to down-regulation of TNF-α and TGF-β production.
Cross-sectional population data suggest that vitamin D deficiency is common in persons with advanced liver disease. [10], [11] For example, Fisher et al. [12] evaluated vitamin D levels in 100 patients with liver disease, 51 with cirrhosis and 49 without cirrhosis, including 38 patients with chronic hepatitis C. The prevalence of vitamin D deficiency was significantly higher in cirrhotic than noncirrhotic subjects (86.3% versus 49.0%, p = 0.0001). Moreover, vitamin D levels decreased with advancing Child class; vitamin D levels were significantly lower in subjects with Child class C (22.7 nmol/L) than in those with Child class A (45.8 nmol/L, p<0.001). Such studies, however, are limited by their cross-sectional nature. Thus, while an association between vitamin D deficiency and advancing liver disease has been noted, the potential that vitamin D deficiency could be a predictor for progressive liver disease has not been explored.
Recently, vitamin D has been evaluated as a potential immunomodulator of hepatitis C virus (HCV), and preliminary data suggest that the addition of vitamin D to standard antiviral therapy may improve treatment response rates. [13] This observation lends further weight to the potential immunomodulatory role of vitamin D in liver disease.
The progression of hepatic fibrosis occurs over years, hampering the study of processes that affect fibrosis. On the other hand, the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial provided a unique opportunity to study fibrosis longitudinally over several years. [14] The HALT-C Trial was a 10-clinical center randomized, controlled trial to evaluate the benefit of long-term (3.5-years) peginterferon therapy in patients with histologically advanced (Ishak fibrosis stage ≥3) but clinically compensated chronic hepatitis C who had failed to respond previously to antiviral therapy. While the HALT-C Trial was a negative study, showing that such maintenance antiviral therapy was ineffective, the trial's study design, including sequential liver biopsies spanning 4 years rendered the trial population ideally suited for the study factors that might influence fibrosis progression. Therefore, we conducted a nested case-control study of vitamin D levels in subjects with and without liver histologic progression or clinical decompensation over the course of the HALT-C Trial.
Abstracts
Source: Gastrohep News
Genetic mutations that protect against fibrosis in HCV
IL28B alleles associated with poor hepatitis C virus clearance protect against inflammation and fibrosis in patients infected with non-1 HCV genotypes, reports the latest issue of Hepatology.
Genetic polymorphisms near IL28B are associated with spontaneous and treatment-induced clearance of hepatitis C virus (HCV), 2 processes that require the appropriate activation of the host immune responses.
Intrahepatic inflammation is believed to mirror such activation, but its relationship with IL28B polymorphisms has yet to be fully appreciated.
Dr Francesco Negro and colleagues from Switzerland analyzed the association of IL28B polymorphisms with histological, and follow-up features in 2335 chronically HCV-infected Caucasian patients.
The G allele at IL28B marker rs8099917 was associated with lower fibrosis
Hepatology
Assessable phenotypes before any antiviral treatment included necroinflammatory activity, fibrosis, fibrosis progression rate, and hepatocellular carcinoma development.
The team evaluated associations of alleles with the phenotypes by univariate analysis and multivariate logistic regression, accounting for all relevant covariates.
The researchers found that the rare G allele at IL28B marker rs8099917 was associated with lower activity, lower fibrosis with a trend toward lower fibrosis progression rate.
When stratified according to HCV genotype, most significant associations were observed in patients infected with non-1 genotypes, where the odds ratio of having necroinflammation or rapid fibrosis progression for patients with IL28B genotypes TG or GG versus TT were 0.48, and 0.56, respectively.
The research team noted that IL28B polymorphisms were not predictive of the development of hepatocellular carcinoma.
De Negro's team concludes, "In chronic hepatitis C, IL28B variants associated with poor response to interferon therapy may predict slower fibrosis progression, especially in patients infected with non-1 HCV genotypes."
Hepatology 2012: 55(2): 384–394
27 February 2012
27 February 2012
Big Pharma
INTERVIEW: Medivir Vies For Spot In Narrow Hepatitis C Market
By Simon Varcoe
LONDON (Dow Jones)--Hepatitis C, a harrowing infection that leads to the inflammation of the liver, is a virus of pandemic size that has attracted the attention of some of the world's biggest drug makers.
But Sweden's small biotech Medivir AB (MVIR-B.SK) says it intends to be a major player in treating the disease, and predicts the market will ultimately have room for just four or five products.
"It is simply a question of which drug will have the biggest share of the market", Medivir's executive vice-president of corporate affairs Rein Piir told Dow Jones Newswires in an interview.
And in protease inhibitor TMC435, Piir believes Medivir has found its winner.
Piir says there is nothing in development that's better than TMC435, which is currently in global Phase III trials and which Medivir expects to launch by the end of next year.
Danske Banke analyst Hans Jeppsson agrees.
Jeppsson regards TMC435 as being the best-in-class protease inhibitor, which prevents viral replication by inhibiting the activity of protease enzymes. Final judgment will need to await results from two combination trials the drug is currently undergoing, he adds.
Around 170 million people are infected worldwide with Hepatitis C, a disease that can be transmitted sexually, through shared needles or through infected blood transfusions.
Thousands of people in Japan were infected with Hepatitis C between the 1970s and 1990s due to tainted blood clotting agents and the country remains one of the most hepatitis C-dense in the world. Due to the high numbers of hepatitis C sufferers in Japan, the country is "as important commercially" to Medivir as Europe, Piir says.
Other countries with a high prevalence of Hepatitis C include Egypt, where around 20% of blood donors are anti-HCV positive, and areas of Italy.
Medivir's Piir believes that the future treatment of Hepatitis C will involve a combination of protease inhibitors; inhibitors of nucleotides, which are molecules that, when joined together, make up the structural units of RNA and DNA; and inhibitors of NS5A, a non structural viral protein found in Hepatitis C.
NS5A inhibitors currently in development include Bristol-Myers Squibb's (BMY) BMS790052, and Gilead Sciences Inc's (GILD) GS-7977. However, Gilead recently reported that a majority of patients in a clinical trial of GS-7977 had experienced a relapse in their disease after being treated with the product, raising questions about the market potential of the drug and the wider class of NS5A inhibitors.
A protease inhibitor currently used to treat HCV genotype 1 infection, the most common and hardest-to-treat type of Hepatitis C is Vertex Pharmaceuticals' (VRTX) and Johnson & Johnson's (JNJ) telaprevir, though, unlike TMC435, it must be administered in combination with pegylated interferon alpha and the antiviral drug ribavirin. Its safety profile has also been criticized, whereas TMC435 has to-date been generally safe and well tolerated, according to Medivir.
The Swedish biotech floated on the Nasdaq OMX Stockholm index in 1996 and currently has a market capitalization of around SEK2.1 billion ($320.2 million).
-By Simon Varcoe, Dow Jones Newswires; +44-20-7842-9449; simon.varcoe@dowjones.com
Related @ NATAP- Download PDF here
Antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2 to 6: TMC435-C202, a phase IIa, open-label study - Article in Press.
Hepatitis C Remains A Hot Play
Source-Seeking Alpha
Novartis (NVS) is preparing to enter the thriving hepatitis C market by licensing rights to Enanta Pharmaceuticals’ lead experimental HCV inhibitor
“We believe EDP-239 has great potential as a potent ingredient in combination drug therapy, and our preclinical studies have demonstrated high potency against multiple genotypes of the virus, excellent safety profile, and a preclinical pharmacokinetic profile amenable to once-a-day dosing in humans,” said Jay Luly, president and CEO of Enanta Pharmaceuticals.
Source-Pharmalot
A new study suggests that research funded by drugmakers is no more biased in favor of new medicines than studies that are funded by the federal government or non-profit foundations.
Diabetes
Diabetes drug improves glucose control without increasing risk of hypoglycemia
University of Michigan leads study showing TAK-875 helps control blood sugar in type 2 diabetes by boosting insulin
TAK-875, a new treatment for type 2 diabetes, improves blood sugar control and is equally effective as glimepiride, but has a significantly lower risk of creating a dangerous drop in blood sugar, called hypoglycemia, according to a new study.
The results of the phase 2 randomized trial were published Online First Sunday in The Lancet.
Type 2 diabetes is the most common form of diabetes accounting for 90 percent of the 150 million people in the United States currently living with the disease. It is primarily caused by a lack of response to insulin which leads to high blood sugar and a variety of chronic conditions.
Free fatty acid receptor 1, also known as G protein-coupled receptor 40, or GPR40, plays a vital role in stimulating and regulating the production of insulin.
It works by boosting the release of insulin from pancreatic β-cells when glucose and fatty acids rise in the blood, such as after a meal, which results in a fall in blood glucose levels. Drugs that activate the FFAR1 receptor have the potential to help diabetics release more insulin and improve control of blood glucose levels.
TAK-875 is a novel oral medication designed to enhance insulin secretion in a glucose-dependant manner, which means that it has no effect on insulin secretion when glucose levels are normal, and as such has the potential to improve the control of blood sugar levels without the risk of hypoglycemia.
In the study, Charles Burant, M.D., Ph.D., professor of internal medicine at the University of Michigan Health System, and colleagues randomly assigned 426 patients with type 2 diabetes who were not achieving adequate glucose control through diet, exercise or metformin treatment to one of five doses of TAK-875, a placebo, or glimepiride, a conventional diabetes treatment. The primary outcome was change in hemogloblin A1c from the start of the study.
At 12 weeks, all doses of TAK-875 resulted in significant drops in HbA1c compared with placebo. A similar reduction occurred in patients given glimepiride.
At a TAK-875 dose of 25 mg or higher, about twice as many patients (33 to 48 percent) reached the American Diabetics Association target of HbA1c less than 7 percent within 12 weeks, compared with placebo (19 percent) and was similar to glimepiride (40 percent).
TAK-875 was generally well-tolerated. The incidence of hypoglycaemia was significantly lower for all doses of TAK-875 compared with glimepiride (2 percent compared to 19 percent), and was similar to placebo which was 2 percent.
The overall incidence of treatment-related side effects was similar for the TAK-875 groups and placebo groups (49 percent; all TAK-875 groups vs 48 percent), but higher in the glimepiride group (61 percent) because of the increased risk of hypoglycaemia.
The authors say: “In view of the frequent hypoglycemia after treatment with sulfonylureas,the low-risk of hypoglycaemia after treatment with TAK-875 suggests that there may be therapeutic advantage of targeting FFAR1 in treating people with type 2 diabetes.”
They conclude:“We are truly excited about the potential of TAK-875 and are eager to conduct larger trials to find out how well this drug works, how safe it is and what its place is in the treatment of diabetes.
“TAK-875 significantly improved glycemic control in patients with type 2 diabetes with minimum risk of hypoglycemia. The results show that activation of FFAR1 is a viable therapeutic target for treatment of type 2 diabetes,” authors say.
Disclosure: Burant is an unpaid consultant and advisor to Takeda Global Research and Development which discovered TAK-875.
Reference: To see the abstract online go to http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61879-5/abstract
Press release courtesy The Lancet
The results of the phase 2 randomized trial were published Online First Sunday in The Lancet.
Type 2 diabetes is the most common form of diabetes accounting for 90 percent of the 150 million people in the United States currently living with the disease. It is primarily caused by a lack of response to insulin which leads to high blood sugar and a variety of chronic conditions.
Free fatty acid receptor 1, also known as G protein-coupled receptor 40, or GPR40, plays a vital role in stimulating and regulating the production of insulin.
It works by boosting the release of insulin from pancreatic β-cells when glucose and fatty acids rise in the blood, such as after a meal, which results in a fall in blood glucose levels. Drugs that activate the FFAR1 receptor have the potential to help diabetics release more insulin and improve control of blood glucose levels.
TAK-875 is a novel oral medication designed to enhance insulin secretion in a glucose-dependant manner, which means that it has no effect on insulin secretion when glucose levels are normal, and as such has the potential to improve the control of blood sugar levels without the risk of hypoglycemia.
In the study, Charles Burant, M.D., Ph.D., professor of internal medicine at the University of Michigan Health System, and colleagues randomly assigned 426 patients with type 2 diabetes who were not achieving adequate glucose control through diet, exercise or metformin treatment to one of five doses of TAK-875, a placebo, or glimepiride, a conventional diabetes treatment. The primary outcome was change in hemogloblin A1c from the start of the study.
At 12 weeks, all doses of TAK-875 resulted in significant drops in HbA1c compared with placebo. A similar reduction occurred in patients given glimepiride.
At a TAK-875 dose of 25 mg or higher, about twice as many patients (33 to 48 percent) reached the American Diabetics Association target of HbA1c less than 7 percent within 12 weeks, compared with placebo (19 percent) and was similar to glimepiride (40 percent).
TAK-875 was generally well-tolerated. The incidence of hypoglycaemia was significantly lower for all doses of TAK-875 compared with glimepiride (2 percent compared to 19 percent), and was similar to placebo which was 2 percent.
The overall incidence of treatment-related side effects was similar for the TAK-875 groups and placebo groups (49 percent; all TAK-875 groups vs 48 percent), but higher in the glimepiride group (61 percent) because of the increased risk of hypoglycaemia.
The authors say: “In view of the frequent hypoglycemia after treatment with sulfonylureas,the low-risk of hypoglycaemia after treatment with TAK-875 suggests that there may be therapeutic advantage of targeting FFAR1 in treating people with type 2 diabetes.”
They conclude:“We are truly excited about the potential of TAK-875 and are eager to conduct larger trials to find out how well this drug works, how safe it is and what its place is in the treatment of diabetes.
“TAK-875 significantly improved glycemic control in patients with type 2 diabetes with minimum risk of hypoglycemia. The results show that activation of FFAR1 is a viable therapeutic target for treatment of type 2 diabetes,” authors say.
Disclosure: Burant is an unpaid consultant and advisor to Takeda Global Research and Development which discovered TAK-875.
Reference: To see the abstract online go to http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61879-5/abstract
Press release courtesy The Lancet
Monday, February 13, 2012
Antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2 to 6: TMC435-C202, a phase IIa, open-label study
Antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2 to 6: TMC435-C202, a phase IIa, open-label study
Journal of Hepatology Feb 12 2012
Christophe Moreno, Thomas Berg, Tawesak Tanwandee, Satawat Thongsawat, Hans Van Vlierberghe, Stefan Zeuzem, Oliver Lenz, Monika Peeters, Vanitha Sekar, Goedele De Smedt
1Department of Gastroenterology and Hepatopancreatology, Hopital Erasme, Universite Libre de Bruxelles, Brussels, Belgium
2Department of Hepatology, Clinic of Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig, Germany
3Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand 4Chiang Mai University, Chiang Mai, Thailand
5Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium
6Department of Medicine I, J.W. Goethe University Hospital, Frankfurt, Germany
7Tibotec, Beerse, Belgium
Abstract
Background & Aims
TMC435 is an investigational, once-daily, oral NS3/4A protease inhibitor currently in phase III development for the treatment of hepatitis C virus (HCV) infection. Phase I and II studies in patients infected with HCV genotype 1 have demonstrated that TMC435 is generally well tolerated, has a pharmacokinetic profile that supports once daily dosing, and demonstrates potent antiviral activity. This phase IIa study (TMC435-C202; NCT00812331) was conducted to investigate the antiviral activity, safety, tolerability, and pharmacokinetics of TMC435 in treatment-naïve patients infected with HCV genotypes 2 to 6.
Methods
The study consisted of 7 days of monotherapy with TMC435 (200 mg once daily). Patients could begin treatment with pegylated interferon/ribavirin from Day 8 with a follow-up period up to Days 37-42.
Results
Thirty-seven patients were enrolled in Germany, Belgium and Thailand. For the primary endpoint at Day 8, the mean (±standard error) change in plasma HCV ribonucleic acid (log10 IU/mL) from baseline was greatest for genotypes 6 (-4.35±0.29) and 4 (-3.52±0.43), followed by genotypes 2 (-2.73±0.71) and 5 (-2.19±0.39). No antiviral activity was evident for genotype 3. Viral breakthrough occurred in six patients during the monotherapy phase and in six additional patients during PegIFN/RBV-only period. All adverse events were mild or moderate and there were no discontinuations during the TMC435 monotherapy period.
Conclusions
The results of this phase IIa proof-of-concept trial provide evidence that TMC435 has a spectrum of activity against multiple HCV genotypes, except for genotype 3. In this study, TMC435 was generally safe and well tolerated.
Introduction
The hepatitis C virus (HCV) is a single-stranded RNA virus and one of the leading causes of chronic liver disease worldwide [1]. It is estimated that 130-170 million people are infected with HCV, constituting 2.2-3.0% of the global population [2]. HCV can be classified into six major genotypes based on sequence divergence of 30% [3]. Genotype 1 has a broad global distribution [4-10]. Genotype 2 is prevalent in North America, Europe and Japan (subtypes 2a and 2b), Northern Italy (2c) [11], and Western Africa [12]. Genotype 3 is noted for its wide distribution among intravenous drug users in a number of countries [13-15], and is also predominant in India and Pakistan [16]. Genotype 4 is responsible for >90% of HCV infections in Egypt, where it is associated with the re-use of needles during mass administration of parenteral antischistosomal therapy until the 1980s, and is also prevalent in other regions of the Middle East and sub-Saharan Africa [3,17-19]. In Europe, its prevalence has recently increased due to immigration and transmission between intravenous drug users [17]. Genotype 5 is found most commonly in South Africa, as well as in four regions in France, Spain, Syria and Belgium [3,17]. Genotype 6 is found in South East Asia and surrounding regions where overall HCV prevalence is high [3,20,21].
Recommended treatment for patients infected with non-genotype 1 HCV is pegylated interferon and ribavirin (PegIFN/RBV). Treatment for different genotypes differs slightly, with PegIFN alpha (α) plus weight-based RBV for 48 weeks recommended for genotypes 1, 4 and 6, and PegIFNα plus low-dose RBV (800 mg) for 24 weeks for genotypes 2 and 3 [22-27]. Of note, given the recent approval of the HCV NS3/4A protease inhibitors boceprevir and telaprevir [28,29] the standard of care for genotype 1 is expected to change [27,30].
Sustained virologic resp 1 onse (SVR, undetectable HCV RNA in patient plasma 24 weeks after treatment end) is achieved in approximately 75% of patients infected with genotypes 2 and 3 [31]. Rates with genotypes 4, 5 or 6 are 43-70% [17]. Furthermore, PegIFN/RBV therapy is poorly tolerated in some patients. In randomised trials of PegIFNα/RBV, influenza-like and neuropsychiatric symptoms occurred in up to 24-64% of patients [22,32], adverse events (AEs) led to study discontinuation in 14-32% and dose reduction in 11-42% [22,32], and anemia or neutropenia led to dose reduction in 9-22% and 18-20%, respectively [22,32].
It is, therefore, clear that novel direct-acting antivirals (DAAs) are required to address issues of sub-optimal efficacy, poor tolerability and compliance failures, and to reduce treatment duration. Boceprevir and telaprevir have demonstrated significantly improved virologic outcomes in both treatment-naïve and -experienced genotype 1 patients [28,29]. However, their thrice daily dosing schedule (with food) and increased rates of AEs including anemia and rash, in comparison to PegIFN/RBV, suggest that there is still room for improvement. Furthermore, activity in other genotypes has not been extensively investigated.
TMC435 is an investigational, once-daily oral NS3/4A protease inhibitor currently in phase III clinical development for the treatment of HCV infection. Phase I and II trials in patients infected with HCV genotype 1 have demonstrated that TMC435 is generally well tolerated, has a pharmacokinetic profile that supports once daily (q.d.) dosing, and demonstrates potent antiviral activity and efficacy [33-36]. Given sub-optimal responses to existing treatment options and the worldwide distribution of genotype 1, this genotype is the current focus of the TMC435 clinical development program. A phase IIa study (TMC435-C202; NCT00812331) was also performed in patients infected 1 with genotypes 2 to 6 to assess the antiviral activity of TMC435 against these genotypes.
Data from biochemical protease assays available before the study start indicated that TMC435 is a potent NS3/4A protease inhibitor in genotypes 2, 4, 5 and 6, with a medium inhibitory concentration (IC50) of <13 nM for all HCV NS3/4A enzymes tested [37]. IC50 for genotype 3 was 37 nM [37].
This study assessed antiviral activity, safety, tolerability and pharmacokinetics of TMC435 (200 mg q.d. administered for 7 days as monotherapy) in treatment-naïve patients infected with HCV genotypes 2 to 6.
Results
Patient demographics and baseline characteristics
The trial was conducted from 3 March to 18 November 2009. A total of 37 patients were enrolled (Fig. 1) across Germany, Belgium and Thailand. No major differences in demographics and baseline disease characteristics were observed, except that all patients with genotype 6 were Asian, and median age of patients with genotype 5 was higher compared with other genotype cohorts (Supplementary Table 1). Overall, 11% of patients in the study had cirrhosis (Metavir score F4), including patients infected with genotype 2 (n=1), genotype 3 (n=1) and genotype 5 (n=2). Multiple subtypes were included in cohorts for genotype 2 (2b, 2c, 2i, 2k), genotype 4 (4, 4c, 4d) and genotype 6 (6a, 6c-l, 6j, 6n) (Table 1).
Following the 7-day TMC435 treatment period, all patients started PegIFN/RBV therapy. Thirty-one patients began PegIFN/RBV on Day 8 or 9, whereas one patient with genotype 3 and five with genotype 6 began PegIFN/RBV after Day 9.
Antiviral activity
Change in plasma HCV RNA from baseline
An initial rapid decline in HCV RNA from baseline at Day 3 of TMC435 monotherapy was evident for all patients infected with HCV genotypes 4 to 6, and for three out of six patients with genotype 2 (Figs 2 and 3). Of these three patients, those who responded were infected with subtypes 2b and 2c. At Day 3, the mean (±standard error [SE]) change from baseline in plasma HCV RNA (log10 IU/mL) was greatest for genotypes 6 (-3.57±0.197) and 4 (-3.43±0.167), followed by genotypes 5 (2.71±0.335) and 2 (-2.02±0.625). For the primary endpoint at Day 8, the mean (±SE) change from baseline was greatest for genotypes 6 (-4.35±0.29) and 4 (-3.52±0.43) cohorts, followed by genotypes 2 (-2.73±0.71) and 5 (-2.19±0.39) (Figs 1 and 2). However, no clear antiviral activity was evident for patients with genotype 3 (change from baseline at day 3 and 8; Figs 2 and 3). At Day 8, four patients (two patients with genotype 4 and two with genotype 6) achieved HCV RNA levels of <25 IU/mL detectable. No patients achieved HCV RNA levels of <25 IU/mL undetectable at Day 8.
From Day 8 to the end of follow-up 2 (Days 37-42), when patients had been treated with PegIFN/RBV only for up to 35 days, mean HCV RNA declined in all genotypes, with the exception of genotype 4 where mean HCV RNA began to increase (Fig. 2). By the end of follow-up 2, HCV RNA change from baseline was -5.19±0.37 for genotype 2, -4.96±0.37 for genotype 3, -3.26±0.77 for genotype 4, -3.89±0.60 for genotype 5 and -5.46±0.32 for genotype 6. HCV RNA was <25 IU/mL detectable for 5/6 (83%), 6/8 (75%), 5/8 (63%), 2/7 (29%) and 7/8 (88%) of patients with genotypes 2, 3, 4, 5 and 6, respectively. HCV RNA <25 IU/mL undetectable was achieved by 5/6 (83%), 3/8 (38%), 5/8 (63%), 1/7 (14%) and 6/8 (75%) of patients with genotypes 2, 3, 4, 5 and 6, respectively.
Viral breakthrough
One patient infected with genotype 3, two with genotype 4 and three with genotype 5 experienced viral breakthrough during the TMC435 monotherapy period. In addition, another 6 patients experienced viral breakthrough during the follow-up period, whilst being treated with PegIFN/RBV only, suggesting lack of activity of PegIFN/RBV treatment in these patients: two infected with genotype 2, one with genotype 3, one with genotype 4, and two with genotype 6.
In genotype 2 and 3-infected patients with viral breakthrough, viral sequencing did not reveal emerging mutations. However, for most genotype 4, 5, and 6 patients with viral breakthrough, emerging mutations were detected. The most frequently observed emerging mutations in the NS3 protease domain were R155K, D168E and D168V (data not shown).
Safety and tolerability
The type and incidence of AEs (all Grade 1-2) during the 7-day TMC435 monotherapy period was similar across all cohorts in the study (Table 2) and the most common AEs were influenza-like illness and headache. There were no clinically relevant changes in laboratory parameters, and no clinically significant findings in terms of vital signs, physical examinations or ECG recordings. Mild elevations in bilirubin (total, direct and indirect) levels were observed in all cohorts. Mean change from baseline to Day 8 was 1.38 μmol/L (95% confidence interval [CI] 0.88, 1.87) for direct and 3.06 μmol/L (95% CI 1.51, 4.61) for indirect bilirubin. These returned to baseline value after completion of TMC435 dosing and were not associated with clinical symptoms or elevations in aspartate aminotransferase, alanine aminotransferase or alkaline phosphatase (Supplementary Table 2).
On Day 8 (after the 7-day dosing period with TMC435 was completed), one patient experienced an SAE of Grade 1 ileitis not considered related to TMC435 therapy. The patient 1 discontinued from the study and recovered after 4 days.
No other discontinuations due to AEs occurred during the trial. Pharmacokinetics Steady-state TMC435 C0h, Cmin, Cmax and AUC24h were similar for the genotype 4, 5 and 6 cohorts, though lower values were observed for the genotype 2 and 3 cohorts with the lowest values in the genotype 3 cohort (Supplementary Table 3). Tmax 6 values were generally similar for all genotype cohorts (Supplementary Table 3). Exposure did not differ according to race or cirrhosis (data not shown).
Discussion
The results of this phase IIa proof-of-concept trial provide evidence that TMC435 has a broad spectrum of activity against multiple HCV genotypes, with the exception of genotype 3.
Monotherapy with oral TMC435 200 mg q.d. for 7 days was associated with potent antiviral activity in patients infected with genotypes 2, 4, 5 and 6. The greatest antiviral activity was observed among patients infected with genotypes 4 and 6, followed by genotypes 2 and 5. Of note, potent activity was observed in three patients with genotype 2, with limited activity observed in the other three patients in this cohort. No antiviral activity was seen against genotype 3. Viral breakthrough (protocol defined: plasma HCV RNA increase >1 log10 IU/mL from the lowest reached, or >100 IU/mL in patients whose HCV RNA was previously <25 IU/mL undetectable or detectable) occurred in six patients during the monotherapy phase. Six additional patients had viral breakthrough during the PegIFN/RBV-only period, and could therefore be considered viral rebound after cessation of treatment with TMC435. In this study, TMC435 was generally safe and well tolerated. All AEs were mild to moderate and during the 7-day period of TMC435 monotherapy there were no discontinuations or untoward changes in biochemical parameters. This is the first study in which an HCV protease inhibitor has demonstrated antiviral activity in genotypes 5 and 6. Furthermore, data for genotypes 2, 3 and 4 are limited for other investigational agents. In a phase IIa study, telaprevir combined with PegIFN/RBV showed substantial activity against genotype 2, modest activity against genotype 4 [38] and limited activity against genotype 3 [39]. Of note, unlike nucleotide inhibitors, NS3 protease inhibitors are generally 1 considered to have limited activity in certain genotypes. However, results of this study suggest that the protease inhibitor TMC435 could be efficacious across multiple genotypes, though additional clinical data are required to provide further support.
A limitation of this study relates to the high subtype diversity in genotypes 2, 4 and 6 (such diversity is not observed in genotypes 3 and 5). Not all subtypes were included in this study and the number of patients per subtype was sometimes limited. Importantly, no difference in efficacy between included subtypes was observed in genotypes 4 or 6. The difference in antiviral activity between patients infected with genotype 2 may be caused by the different subtypes, as HCV RNA change from baseline at Day 3 in patients infected with 2b and 2c was -3.19 to -3.61- log10 IU/mL, compared with -0.26 to -0.99 in those infected with 2, 2k and 2i. In addition to this limitation, the sample size in each cohort was relatively small. It should also be noted that a TMC435 dose of 200 mg q.d. was administered in this trial, whereas a dose of 150 mg is currently in phase III development.
The lack of antiviral activity against genotype 3, compared with other genotypes, is consistent with the lower IC50 value of TMC435 against a genotype 3 isolate in an in vitro biochemical assay [37]. It is suggested that this may be due to the presence of a naturally occurring D168Q polymorphism at baseline, which is present in most genotype 3a isolates known to date and was observed in all genotype 3a patients included in this study (data not shown). A D168Q mutation alone has been shown to reduce TMC435 activity in a genotype 1b replicon assay by >700 fold [40]. TMC435 exposure (as indicated by C0h, Cmin, Cmax and AUC24h) was lower in genotypes 2 and 3 than in genotypes 4, 5 and 6, though it is suggested that this may be due to chance due to the small number of patients 1 in this study. Furthermore, as mean AUC values were <3 fold lower in the genotype 3 cohort compared to genotype 6 but in vitro susceptibility of genotype 3 isolates was >700 fold lower, the lower exposure observed in this cohort does not explain the lack of antiviral activity against genotype 3.
In patients infected with HCV genotype 4, mean change from baseline in HCV RNA began to increase after Day 5. Prior to Day 8, this was driven by two patients who experienced viral breakthrough under TMC435 monotherapy. The further increase in HCV RNA after Day 8 is thought to reflect a lack of response to PegIFN/RBV. Novel agents for the treatment of genotypes 4 to 6 would be advantageous as SVR rates are low [17,31], and together with genotype 1 these groups are considered 'difficult to treat'. Antiviral activity against genotypes 4 to 6 observed in this study suggests that TMC435 could provide a clinical benefit, particularly for patients infected with genotypes 4 and 6. For genotype 5, the mean decline in HCV RNA from baseline over the 7 day monotherapy period was slightly lower compared to genotypes 4 and 6, suggesting that the TMC435 activity was somewhat lower in this group. Due to SVR rates of ≥70% in genotype 2 and 3 patients following treatment with PegIFN/RBV, there is perhaps a less urgent need for novel agents to treat infection with these genotypes, though patients who do not respond to treatment could benefit from regimens including novel DAAs. TMC435 showed antiviral activity in 3/6 patients infected with genotype 2, and no activity against genotype 3. Of note, given the high sequence variability between the different genotypes and subtypes, further work is ongoing to investigate the role of naturally occurring baseline polymorphism in variation 1 in virologic response, and to fully characterise viral variants observed in patients with viral breakthrough.
In spite of study limitations outlined above, the results of this phase IIa study in 37 treatment-naïve patients suggest that this investigational agent may be a future candidate for treatment of infection with HCV genotypes 4, 5 and 6, and potentially particular subtypes of genotype 2.
Journal of Hepatology Feb 12 2012
Christophe Moreno, Thomas Berg, Tawesak Tanwandee, Satawat Thongsawat, Hans Van Vlierberghe, Stefan Zeuzem, Oliver Lenz, Monika Peeters, Vanitha Sekar, Goedele De Smedt
1Department of Gastroenterology and Hepatopancreatology, Hopital Erasme, Universite Libre de Bruxelles, Brussels, Belgium
2Department of Hepatology, Clinic of Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig, Germany
3Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand 4Chiang Mai University, Chiang Mai, Thailand
5Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium
6Department of Medicine I, J.W. Goethe University Hospital, Frankfurt, Germany
7Tibotec, Beerse, Belgium
Abstract
Background & Aims
TMC435 is an investigational, once-daily, oral NS3/4A protease inhibitor currently in phase III development for the treatment of hepatitis C virus (HCV) infection. Phase I and II studies in patients infected with HCV genotype 1 have demonstrated that TMC435 is generally well tolerated, has a pharmacokinetic profile that supports once daily dosing, and demonstrates potent antiviral activity. This phase IIa study (TMC435-C202; NCT00812331) was conducted to investigate the antiviral activity, safety, tolerability, and pharmacokinetics of TMC435 in treatment-naïve patients infected with HCV genotypes 2 to 6.
Methods
The study consisted of 7 days of monotherapy with TMC435 (200 mg once daily). Patients could begin treatment with pegylated interferon/ribavirin from Day 8 with a follow-up period up to Days 37-42.
Results
Thirty-seven patients were enrolled in Germany, Belgium and Thailand. For the primary endpoint at Day 8, the mean (±standard error) change in plasma HCV ribonucleic acid (log10 IU/mL) from baseline was greatest for genotypes 6 (-4.35±0.29) and 4 (-3.52±0.43), followed by genotypes 2 (-2.73±0.71) and 5 (-2.19±0.39). No antiviral activity was evident for genotype 3. Viral breakthrough occurred in six patients during the monotherapy phase and in six additional patients during PegIFN/RBV-only period. All adverse events were mild or moderate and there were no discontinuations during the TMC435 monotherapy period.
Conclusions
The results of this phase IIa proof-of-concept trial provide evidence that TMC435 has a spectrum of activity against multiple HCV genotypes, except for genotype 3. In this study, TMC435 was generally safe and well tolerated.
Introduction
The hepatitis C virus (HCV) is a single-stranded RNA virus and one of the leading causes of chronic liver disease worldwide [1]. It is estimated that 130-170 million people are infected with HCV, constituting 2.2-3.0% of the global population [2]. HCV can be classified into six major genotypes based on sequence divergence of 30% [3]. Genotype 1 has a broad global distribution [4-10]. Genotype 2 is prevalent in North America, Europe and Japan (subtypes 2a and 2b), Northern Italy (2c) [11], and Western Africa [12]. Genotype 3 is noted for its wide distribution among intravenous drug users in a number of countries [13-15], and is also predominant in India and Pakistan [16]. Genotype 4 is responsible for >90% of HCV infections in Egypt, where it is associated with the re-use of needles during mass administration of parenteral antischistosomal therapy until the 1980s, and is also prevalent in other regions of the Middle East and sub-Saharan Africa [3,17-19]. In Europe, its prevalence has recently increased due to immigration and transmission between intravenous drug users [17]. Genotype 5 is found most commonly in South Africa, as well as in four regions in France, Spain, Syria and Belgium [3,17]. Genotype 6 is found in South East Asia and surrounding regions where overall HCV prevalence is high [3,20,21].
Recommended treatment for patients infected with non-genotype 1 HCV is pegylated interferon and ribavirin (PegIFN/RBV). Treatment for different genotypes differs slightly, with PegIFN alpha (α) plus weight-based RBV for 48 weeks recommended for genotypes 1, 4 and 6, and PegIFNα plus low-dose RBV (800 mg) for 24 weeks for genotypes 2 and 3 [22-27]. Of note, given the recent approval of the HCV NS3/4A protease inhibitors boceprevir and telaprevir [28,29] the standard of care for genotype 1 is expected to change [27,30].
Sustained virologic resp 1 onse (SVR, undetectable HCV RNA in patient plasma 24 weeks after treatment end) is achieved in approximately 75% of patients infected with genotypes 2 and 3 [31]. Rates with genotypes 4, 5 or 6 are 43-70% [17]. Furthermore, PegIFN/RBV therapy is poorly tolerated in some patients. In randomised trials of PegIFNα/RBV, influenza-like and neuropsychiatric symptoms occurred in up to 24-64% of patients [22,32], adverse events (AEs) led to study discontinuation in 14-32% and dose reduction in 11-42% [22,32], and anemia or neutropenia led to dose reduction in 9-22% and 18-20%, respectively [22,32].
It is, therefore, clear that novel direct-acting antivirals (DAAs) are required to address issues of sub-optimal efficacy, poor tolerability and compliance failures, and to reduce treatment duration. Boceprevir and telaprevir have demonstrated significantly improved virologic outcomes in both treatment-naïve and -experienced genotype 1 patients [28,29]. However, their thrice daily dosing schedule (with food) and increased rates of AEs including anemia and rash, in comparison to PegIFN/RBV, suggest that there is still room for improvement. Furthermore, activity in other genotypes has not been extensively investigated.
TMC435 is an investigational, once-daily oral NS3/4A protease inhibitor currently in phase III clinical development for the treatment of HCV infection. Phase I and II trials in patients infected with HCV genotype 1 have demonstrated that TMC435 is generally well tolerated, has a pharmacokinetic profile that supports once daily (q.d.) dosing, and demonstrates potent antiviral activity and efficacy [33-36]. Given sub-optimal responses to existing treatment options and the worldwide distribution of genotype 1, this genotype is the current focus of the TMC435 clinical development program. A phase IIa study (TMC435-C202; NCT00812331) was also performed in patients infected 1 with genotypes 2 to 6 to assess the antiviral activity of TMC435 against these genotypes.
Data from biochemical protease assays available before the study start indicated that TMC435 is a potent NS3/4A protease inhibitor in genotypes 2, 4, 5 and 6, with a medium inhibitory concentration (IC50) of <13 nM for all HCV NS3/4A enzymes tested [37]. IC50 for genotype 3 was 37 nM [37].
This study assessed antiviral activity, safety, tolerability and pharmacokinetics of TMC435 (200 mg q.d. administered for 7 days as monotherapy) in treatment-naïve patients infected with HCV genotypes 2 to 6.
Results
Patient demographics and baseline characteristics
The trial was conducted from 3 March to 18 November 2009. A total of 37 patients were enrolled (Fig. 1) across Germany, Belgium and Thailand. No major differences in demographics and baseline disease characteristics were observed, except that all patients with genotype 6 were Asian, and median age of patients with genotype 5 was higher compared with other genotype cohorts (Supplementary Table 1). Overall, 11% of patients in the study had cirrhosis (Metavir score F4), including patients infected with genotype 2 (n=1), genotype 3 (n=1) and genotype 5 (n=2). Multiple subtypes were included in cohorts for genotype 2 (2b, 2c, 2i, 2k), genotype 4 (4, 4c, 4d) and genotype 6 (6a, 6c-l, 6j, 6n) (Table 1).
Following the 7-day TMC435 treatment period, all patients started PegIFN/RBV therapy. Thirty-one patients began PegIFN/RBV on Day 8 or 9, whereas one patient with genotype 3 and five with genotype 6 began PegIFN/RBV after Day 9.
Antiviral activity
Change in plasma HCV RNA from baseline
An initial rapid decline in HCV RNA from baseline at Day 3 of TMC435 monotherapy was evident for all patients infected with HCV genotypes 4 to 6, and for three out of six patients with genotype 2 (Figs 2 and 3). Of these three patients, those who responded were infected with subtypes 2b and 2c. At Day 3, the mean (±standard error [SE]) change from baseline in plasma HCV RNA (log10 IU/mL) was greatest for genotypes 6 (-3.57±0.197) and 4 (-3.43±0.167), followed by genotypes 5 (2.71±0.335) and 2 (-2.02±0.625). For the primary endpoint at Day 8, the mean (±SE) change from baseline was greatest for genotypes 6 (-4.35±0.29) and 4 (-3.52±0.43) cohorts, followed by genotypes 2 (-2.73±0.71) and 5 (-2.19±0.39) (Figs 1 and 2). However, no clear antiviral activity was evident for patients with genotype 3 (change from baseline at day 3 and 8; Figs 2 and 3). At Day 8, four patients (two patients with genotype 4 and two with genotype 6) achieved HCV RNA levels of <25 IU/mL detectable. No patients achieved HCV RNA levels of <25 IU/mL undetectable at Day 8.
From Day 8 to the end of follow-up 2 (Days 37-42), when patients had been treated with PegIFN/RBV only for up to 35 days, mean HCV RNA declined in all genotypes, with the exception of genotype 4 where mean HCV RNA began to increase (Fig. 2). By the end of follow-up 2, HCV RNA change from baseline was -5.19±0.37 for genotype 2, -4.96±0.37 for genotype 3, -3.26±0.77 for genotype 4, -3.89±0.60 for genotype 5 and -5.46±0.32 for genotype 6. HCV RNA was <25 IU/mL detectable for 5/6 (83%), 6/8 (75%), 5/8 (63%), 2/7 (29%) and 7/8 (88%) of patients with genotypes 2, 3, 4, 5 and 6, respectively. HCV RNA <25 IU/mL undetectable was achieved by 5/6 (83%), 3/8 (38%), 5/8 (63%), 1/7 (14%) and 6/8 (75%) of patients with genotypes 2, 3, 4, 5 and 6, respectively.
Viral breakthrough
One patient infected with genotype 3, two with genotype 4 and three with genotype 5 experienced viral breakthrough during the TMC435 monotherapy period. In addition, another 6 patients experienced viral breakthrough during the follow-up period, whilst being treated with PegIFN/RBV only, suggesting lack of activity of PegIFN/RBV treatment in these patients: two infected with genotype 2, one with genotype 3, one with genotype 4, and two with genotype 6.
In genotype 2 and 3-infected patients with viral breakthrough, viral sequencing did not reveal emerging mutations. However, for most genotype 4, 5, and 6 patients with viral breakthrough, emerging mutations were detected. The most frequently observed emerging mutations in the NS3 protease domain were R155K, D168E and D168V (data not shown).
Safety and tolerability
The type and incidence of AEs (all Grade 1-2) during the 7-day TMC435 monotherapy period was similar across all cohorts in the study (Table 2) and the most common AEs were influenza-like illness and headache. There were no clinically relevant changes in laboratory parameters, and no clinically significant findings in terms of vital signs, physical examinations or ECG recordings. Mild elevations in bilirubin (total, direct and indirect) levels were observed in all cohorts. Mean change from baseline to Day 8 was 1.38 μmol/L (95% confidence interval [CI] 0.88, 1.87) for direct and 3.06 μmol/L (95% CI 1.51, 4.61) for indirect bilirubin. These returned to baseline value after completion of TMC435 dosing and were not associated with clinical symptoms or elevations in aspartate aminotransferase, alanine aminotransferase or alkaline phosphatase (Supplementary Table 2).
On Day 8 (after the 7-day dosing period with TMC435 was completed), one patient experienced an SAE of Grade 1 ileitis not considered related to TMC435 therapy. The patient 1 discontinued from the study and recovered after 4 days.
No other discontinuations due to AEs occurred during the trial. Pharmacokinetics Steady-state TMC435 C0h, Cmin, Cmax and AUC24h were similar for the genotype 4, 5 and 6 cohorts, though lower values were observed for the genotype 2 and 3 cohorts with the lowest values in the genotype 3 cohort (Supplementary Table 3). Tmax 6 values were generally similar for all genotype cohorts (Supplementary Table 3). Exposure did not differ according to race or cirrhosis (data not shown).
Discussion
The results of this phase IIa proof-of-concept trial provide evidence that TMC435 has a broad spectrum of activity against multiple HCV genotypes, with the exception of genotype 3.
Monotherapy with oral TMC435 200 mg q.d. for 7 days was associated with potent antiviral activity in patients infected with genotypes 2, 4, 5 and 6. The greatest antiviral activity was observed among patients infected with genotypes 4 and 6, followed by genotypes 2 and 5. Of note, potent activity was observed in three patients with genotype 2, with limited activity observed in the other three patients in this cohort. No antiviral activity was seen against genotype 3. Viral breakthrough (protocol defined: plasma HCV RNA increase >1 log10 IU/mL from the lowest reached, or >100 IU/mL in patients whose HCV RNA was previously <25 IU/mL undetectable or detectable) occurred in six patients during the monotherapy phase. Six additional patients had viral breakthrough during the PegIFN/RBV-only period, and could therefore be considered viral rebound after cessation of treatment with TMC435. In this study, TMC435 was generally safe and well tolerated. All AEs were mild to moderate and during the 7-day period of TMC435 monotherapy there were no discontinuations or untoward changes in biochemical parameters. This is the first study in which an HCV protease inhibitor has demonstrated antiviral activity in genotypes 5 and 6. Furthermore, data for genotypes 2, 3 and 4 are limited for other investigational agents. In a phase IIa study, telaprevir combined with PegIFN/RBV showed substantial activity against genotype 2, modest activity against genotype 4 [38] and limited activity against genotype 3 [39]. Of note, unlike nucleotide inhibitors, NS3 protease inhibitors are generally 1 considered to have limited activity in certain genotypes. However, results of this study suggest that the protease inhibitor TMC435 could be efficacious across multiple genotypes, though additional clinical data are required to provide further support.
A limitation of this study relates to the high subtype diversity in genotypes 2, 4 and 6 (such diversity is not observed in genotypes 3 and 5). Not all subtypes were included in this study and the number of patients per subtype was sometimes limited. Importantly, no difference in efficacy between included subtypes was observed in genotypes 4 or 6. The difference in antiviral activity between patients infected with genotype 2 may be caused by the different subtypes, as HCV RNA change from baseline at Day 3 in patients infected with 2b and 2c was -3.19 to -3.61- log10 IU/mL, compared with -0.26 to -0.99 in those infected with 2, 2k and 2i. In addition to this limitation, the sample size in each cohort was relatively small. It should also be noted that a TMC435 dose of 200 mg q.d. was administered in this trial, whereas a dose of 150 mg is currently in phase III development.
The lack of antiviral activity against genotype 3, compared with other genotypes, is consistent with the lower IC50 value of TMC435 against a genotype 3 isolate in an in vitro biochemical assay [37]. It is suggested that this may be due to the presence of a naturally occurring D168Q polymorphism at baseline, which is present in most genotype 3a isolates known to date and was observed in all genotype 3a patients included in this study (data not shown). A D168Q mutation alone has been shown to reduce TMC435 activity in a genotype 1b replicon assay by >700 fold [40]. TMC435 exposure (as indicated by C0h, Cmin, Cmax and AUC24h) was lower in genotypes 2 and 3 than in genotypes 4, 5 and 6, though it is suggested that this may be due to chance due to the small number of patients 1 in this study. Furthermore, as mean AUC values were <3 fold lower in the genotype 3 cohort compared to genotype 6 but in vitro susceptibility of genotype 3 isolates was >700 fold lower, the lower exposure observed in this cohort does not explain the lack of antiviral activity against genotype 3.
In patients infected with HCV genotype 4, mean change from baseline in HCV RNA began to increase after Day 5. Prior to Day 8, this was driven by two patients who experienced viral breakthrough under TMC435 monotherapy. The further increase in HCV RNA after Day 8 is thought to reflect a lack of response to PegIFN/RBV. Novel agents for the treatment of genotypes 4 to 6 would be advantageous as SVR rates are low [17,31], and together with genotype 1 these groups are considered 'difficult to treat'. Antiviral activity against genotypes 4 to 6 observed in this study suggests that TMC435 could provide a clinical benefit, particularly for patients infected with genotypes 4 and 6. For genotype 5, the mean decline in HCV RNA from baseline over the 7 day monotherapy period was slightly lower compared to genotypes 4 and 6, suggesting that the TMC435 activity was somewhat lower in this group. Due to SVR rates of ≥70% in genotype 2 and 3 patients following treatment with PegIFN/RBV, there is perhaps a less urgent need for novel agents to treat infection with these genotypes, though patients who do not respond to treatment could benefit from regimens including novel DAAs. TMC435 showed antiviral activity in 3/6 patients infected with genotype 2, and no activity against genotype 3. Of note, given the high sequence variability between the different genotypes and subtypes, further work is ongoing to investigate the role of naturally occurring baseline polymorphism in variation 1 in virologic response, and to fully characterise viral variants observed in patients with viral breakthrough.
In spite of study limitations outlined above, the results of this phase IIa study in 37 treatment-naïve patients suggest that this investigational agent may be a future candidate for treatment of infection with HCV genotypes 4, 5 and 6, and potentially particular subtypes of genotype 2.
Sunday, November 13, 2011
AASLD: (TMC435)-New PI Effective, Safe in HCV Trial
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| Action Points
SAN FRANCISCO -- An investigational hepatitis C virus (HCV) drug -- a second-generation protease inhibitor given once a day -- was safe and effective in a phase IIB randomized trial, a researcher said here. Between 75% and 86% of patients treated with TMC435 had undetectable hepatitis C RNA after 24 weeks of treatment, depending on dose, reported Michael Fried, MD, of the University of North Carolina in Chapel Hill. In addition, there was no major difference in adverse events between the treatment and placebo arms in the PILLAR (Protease Inhibitor TMC435 trial assessing the optimaL dose and duration as once daiLy Anti-viral Regimen) trial, Fried said at a late-breaker session during the annual meeting of the American Association for the Study of Liver Diseases. The primary endpoint of the study was the proportion of patients with undetectable hepatitis C RNA at week 72, which was 24 weeks after the end of treatment, Fried said. However, his presentation here focused on what he said was "the most clinically meaningful endpoint," which was the rate of undetectable hepatitis C RNA at week 24. The researchers enrolled 386 patients with the difficult-to-treat genotype 1 of hepatitis C and randomly assigned them to placebo or one of two doses of TMC435: 75 or 150 mg daily. All patients were also given standard therapy with pegylated interferon-alfa and ribavirin for at least the first 24 weeks of the study. Depending on response, some patients in the treatment arms stopped the treatment or were given an additional 24 weeks. Patients in the control arm had 48 weeks of interferon and ribavirin. Within each TMC435 dosing group, patients were randomly assigned to get 12 or 24 weeks of the drug. In an intention-to-treat analysis, the researchers found:
Interestingly, the 75% response in the 24-week, 75-mg arm was not significantly different from the "unexpectedly high" 65% response rate among the placebo patients, Fried said. A key finding was that between 79% and 86% of the patients receiving the drug qualified for shortened 24-week therapy, "which I think is quite beneficial," Fried said. Of those, he said, between 85% and 96% had undetectable hepatitis C RNA at week 24. All patients had at least one adverse event, Fried said, with 3.6% of such events leading to study discontinuation in the TMC435 arms, compared with 5.2% in the control arm. The rate of grades 3 and 4 events was similar between the treatment and placebo arms. However, 6.5% of adverse events were judged as serious in the TMC435 group compared with 13% among placebo patients. Most adverse events, including rash, anemia, and neutropenia, were similar between the arms. The compound is the "front-runner" in the second generation of protease inhibitors and clinicians are watching its progress closely, according to Norah Terrault, MD, of the University of California San Francisco, who was not part of the study but was one of the moderators of the session at which it was presented. "This is the next step for us if we are going to use peginterferon and ribavirin," she told MedPage Today. "It is clearly going to offer an advantage over current therapies." One advantage, she said, is that once-daily dosing -- compared with three times a day for the currently approved drugs -- should improve patient adherence to their treatment regimen. As well, she added, the "side effect profile looks very good" with no additional burden of rash or anemia. On the other hand, a range of new drugs is in development and some can be given without interferon. Clinicians may soon be able to choose interferon-free strategies to treat hepatitis C, Terrault said. The study was supported by Tibotec. Fried reported financial links with GSK, Roche, Merck, Tibotec, Vertex, Abbott, Pharmasset, Anadys, and Bristol-Myers Squibb. Terrault reported financial links with Gilead, Pfizer, Genentech, Roche, SciClone, BMS, Novartis, Essai, and Vertex. | ||
| Primary source: Hepatology Source reference: Fried M, et al. "TMC435 in combination with peginterferon and ribavarin in treatment-naive HCV genotype 1 patients: Final analysis of the PILLAR Phase IIB study" Hepatology 2011; Abstract LB-5. http://www.medpagetoday.com/MeetingCoverage/AASLD/29639 |
Saturday, November 5, 2011
AASLD-Phase 2b PILLAR Study of Once-Daily TMC435
Tibotec to Present Final Safety and Efficacy Results From Phase 2b PILLAR Study of Once-Daily TMC435 in Late-Breaker at AASLD
-- Data show high rates of virologic response and shortened treatment duration; safety and tolerability comparable to placebo --
SAN FRANCISCO, Nov. 5, 2011 /PRNewswire/ -- Tibotec Pharmaceuticals (Tibotec), one of the Janssen (Janssen) Pharmaceutical Companies, today will present results of the final analysis of PILLAR, a phase 2b study of the investigational hepatitis C virus (HCV) NS3/4A protease inhibitor
TMC435 in treatment-naive patients with chronic genotype 1 HCV, as part of a late-breaker oral presentation at the 62nd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in San Francisco, CA, USA.
Results from the final PILLAR analysis showed that TMC435 administered in combination with peginterferon alpha-2a and ribavirin (PR) resulted in significantly higher sustained virologic response (SVR) rates compared to placebo plus PR. In the two TMC435 treatment groups who received TMC435 75mg, between 75 and 82 percent of patients achieved SVR24, and in the two TMC435 treatment groups who received TMC435 150mg, between 81 and 86 percent of patients achieved SVR24. This is compared to 65 percent of patients in the placebo arm who achieved SVR24. In addition, 79 to 86 percent of patients in the TMC435 treatment arms had a shortened treatment duration of 24 weeks, compared to a 48 weeks treatment duration for patients who received placebo plus P/R. In TMC435 arms, 68 to 76 percent of patients achieved rapid virologic response [RVR; HCV RNA less then 25 (undetectable)], of whom 88 to 95 percent achieved SVR24. There were no significant differences for adverse events between TMC435 treatment groups and placebo.
TMC435 150mg administered once daily (q.d.) is being investigated in phase 3 trials in treatment-naive patients and in patients who experienced a viral relapse after being treated with interferon-based therapy. TMC435 is being developed by Tibotec Pharmaceuticals. Medivir AB has commercialization rights for TMC435 for the Nordic countries, Janssen has commercialization rights for TMC435 in the rest of the world.
The PILLAR study [Protease Inhibitor TMC435 trial assessing the optimaL dose and duration as once daiLy Anti-viral Regimen] (TMC435-C205; NCT00882908) was a five-arm, global phase 2b randomized, double-blind, placebo controlled study in 386 treatment-naive patients. TMC435 was administered in doses of 75mg or 150mg q.d. for either 12 weeks or 24 weeks in combination with 24 or 48 weeks of peg-interferon and ribavirin (PR). Patients in the placebo arm receive 24 weeks of placebo plus peg-interferon and ribavirin followed by 24 additional weeks of peg-interferon and ribavirin treatment. The primary endpoint of the study was sustained virologic response at Week-72 (SVR week 72). The PILLAR study was conducted in 13 countries in Europe, North America, and Australasia.
Patients receiving TMC435 were allowed to stop all treatment at week 24 if they met both response-guided criteria: a) detectable or undetectable HCV RNA levels (Less then 25 IU/mL) at week 4 and b) undetectable HCV RNA at weeks 12, 16 and 20. Patients who did not meet the above response-guided criteria continued with peg-interferon and ribavirin until Week-48.
"HCV is a devastating problem worldwide and remains a leading cause of cirrhosis, liver cancer, and liver transplantation," said Dr. Michael W. Fried M.D., lead clinical investigator and Professor of Medicine, Director, UNC Liver Center, University of North Carolina at Chapel Hill. "We are extremely encouraged by the success of once-daily TMC435 in achieving significantly higher SVR compared to control group and look forward to furthering its development in recently launched phase 3 trials."
The goal of HCV treatment is to achieve SVR24, which means the virus is undetectable in patients' blood six months after they have finished treatment. Patients who achieve SVR are considered cured.
The most common adverse events (AEs) in the PILLAR study were headache and fatigue, 46 percent and 42 percent in the TMC435 groups and 51 percent and 47 percent in the placebo group respectively. There were no clinically significant differences in frequency of rash, anemia or gastrointestinal events between the TMC435 groups and placebo. Most AEs were mild to moderate in severity.
AEs leading to treatment discontinuation of TMC435/placebo were reported in 7.1 percent of patients in TMC435 arms and 7.8 percent in placebo arm.
"Tibotec is pleased to present the final results of the phase 2b PILLAR study at AASLD. The continued development of TMC435, which is currently being investigated in registrational phase 3 studies reinforces our strong commitment to the development of new therapies that may reduce treatment duration and improve the lives of those impacted by HCV," said Maria Beumont, M.D., Global Medical Leader TMC435 at Tibotec.
In conjunction with the final sustained virologic response (SVR) results from PILLAR, Tibotec is presenting virology analysis data from PILLAR and two sets of early study results on the effects of co-administering TMC435 and methadone and its interaction with the antidepressant escitalopram, to be featured in 3 posters at AASLD:
"TMC435 in combination with peginterferon alpha-2a/ribavirin in treatment-naive patients infected with HCV genotype 1: virology analysis of the PILLAR study." O. Lenz.
"The pharmacokinetic interaction between the investigational NS3-4A HCV protease inhibitor TMC435 and methadone." M. Beumont-Mauviel.
"The pharmacokinetic interaction between the investigational HCV NS3/4A protease inhibitor TMC435 and escitalopram." M. Beumont-Mauviel.
Tibotec is currently conducting two global, phase 3 registrational trials to examine TMC435 in treatment-naive adults with chronic genotype 1 hepatitis C virus (HCV). A third global, phase 3 trial is being conducted in genotype 1 HCV patients who have experienced a viral relapse after prior interferon-based treatment. All three studies are fully randomized.
About HCVHCV is a blood-borne infectious disease that affects the liver. With an estimated 170 million people infected worldwide and three to four million people newly infected each year, HCV puts a significant burden on patients and society. Chronic infection with HCV can lead to liver cancer and other serious and fatal liver diseases, and is the most common cause of liver transplant worldwide. Pegylated interferon combined with ribavirin causes serious side effects and only cures 40 to 50 percent of genotype 1 patients. The development of new therapies, particularly direct antivirals with different modes of action, may allow HCV patients to undergo a shorter and more effective treatment regimen.
About Tibotec Pharmaceuticals Tibotec Pharmaceuticals, one of the Janssen Pharmaceutical Companies of Johnson & Johnson, is a global pharmaceutical and research development company. The Company's main research and development facilities are in Beerse, Belgium with offices in Titusville, NJ and Cork, Ireland. Tibotec is dedicated to the discovery and development of innovative HIV/AIDS and hepatitis C drugs, and anti-infectives for diseases of high unmet medical need.
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SOURCE Tibotec Pharmaceuticals
(Source: PR Newswire )(Source: Quotemedia)
Wednesday, November 2, 2011
TMC435 Phase IIb ASPIRE (C206) Study-Final Results
Medivir Announces Final Results from TMC435 Phase IIb ASPIRE (C206) Study
Groups (150 mg q.d.) vs Placebo
............................All
......TMC435 TMC435 TMC435 TMC435
.................................Placebo
......12PR48 24PR48 48PR48 PR48..PR48
% (n/N)
.......N=66 N=68 N=65 N=199 N=66
........76.9 88.9 88.5 84.8 37.0
Relapsers SVR24 (20/26) (24/27) (23/26) (67/79) (10/27)
Partial.......... 65.2.. 75.0.....86.4....75.3.. 8.7
Responders SVR24.(15/23) (18/24) (19/22) (52/69)(2/23)
Null...............52.9...41.2... 58.8....51.0...18.8
Responders SVR24...9/17) (7/17) (10/17) (26/51) (3/16)
TMC435-Based Therapy Significantly Improved Viral Cure Rates in Patients Who Failed Prior Treatment for Hepatitis C
- ASPIRE: All TMC435 subgroups achieved substantially higher viral cure rates (SVR24) compared with control group (pegylated interferon and ribavirin alone): 85% vs. 37% in prior relapsers, 75% vs. 9% in prior partial responders and 51% vs. 19% in prior null responders -
- Once daily TMC435 was generally safe and well tolerated at all doses and treatment durations -
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HUDDINGE, Sweden, Nov 02, 2011 (BUSINESS WIRE) -- Regulatory News:
TMC435-Based Therapy Significantly Improved Viral Cure Rates in Patients Who Failed Prior Treatment for Hepatitis C
- ASPIRE: All TMC435 subgroups achieved substantially higher viral cure rates (SVR24) compared with control group (pegylated interferon and ribavirin alone): 85% vs. 37% in prior relapsers, 75% vs. 9% in prior partial responders and 51% vs. 19% in prior null responders --
- Once daily TMC435 was generally safe and well tolerated at all doses and treatment durations -
Medivir AB (omx:MVIR), a research-based speciality pharmaceutical company focused on infectious diseases, today announces final results from the ASPIRE study. This phase IIb study evaluated TMC435 once daily in addition to pegylated interferon (PegIFN) and ribavirin (RBV) in patients with genotype-1 chronic hepatitis C whose prior treatment with PegIFN and RBV was unsuccessful either because they relapsed, had a partial response or had a null response.
Data from the ASPIRE study showed that patients in each of these subgroups who were treated with TMC435-based combination therapy achieved superior rates of sustained virologic response (viral cure) compared with those retreated with PegIFN and RBV alone.
Charlotte Edenius, Executive VP Research and Development, of Medivir commented, "We are extremely pleased with the final results from the ASPIRE study showing high viral cure rates and a favourable safety and tolerability profile in these difficult to treat genotype-1 hepatitis C patients whose prior treatment was unsuccessful. These results may provide new optimism for people who have failed on previous therapy, including those with advanced liver disease. We are highly committed to the broad and rapid development of TMC435 and global pivotal phase III clinical trials are currently well underway"
ASPIRE (C206) -- Design TMC435, a potent, once-daily, oral hepatitis C virus protease inhibitor, is being developed by Tibotec jointly with Medivir. The randomized, placebo-controlled, double-blind ASPIRE study evaluates the effect of TMC435 in combination with pegylated-interferon and ribavirin in 462 patients infected with genotype-1 hepatitis C virus who have failed prior treatment with PegIFN/RBV. The primary endpoint was proportion of patients with undetectable HCV RNA 24 weeks after the planned end of treatment (SVR24).
The study includes patients who have relapsed, achieved partial response, or achieved no response (null responders) to PegIFN/RBV treatment. 62 percent (287/462) of patients had advanced liver disease, periportal or septal fibrosis or cirrhosis (scarring of the liver) upon study entry (Metavir score F2-F4).
Patients were equally randomized to one of seven different treatment arms, six TMC435 treatment arms and one placebo arm. TMC435 was administered once daily at a dose of either 100 mg or 150 mg given for either 12, 24, or 48 weeks in combination with 48 weeks of PegIFN/RBV. The results are based on the intent-to-treat (ITT), population which included all randomized patients who took at least one dose of the study medication.
Results - Efficacy In this final analysis, all subgroups of treatment-experienced patients who failed previous PegIFN and RBV treatment, achieved substantially higher virologic response rates following treatment with TMC435-containing regimen at all doses and durations, compared with PegIFN and RBV alone.
Regardless of treatment duration all TMC435 treatment arms showed significantly improved effect on SVR24 versus PegIFN/RBV alone.
Sustained Virologic Response (SVR24) Rates in TMC435 DoseGroups (150 mg q.d.) vs Placebo
............................All
......TMC435 TMC435 TMC435 TMC435
.................................Placebo
......12PR48 24PR48 48PR48 PR48..PR48
% (n/N)
.......N=66 N=68 N=65 N=199 N=66
........76.9 88.9 88.5 84.8 37.0
Relapsers SVR24 (20/26) (24/27) (23/26) (67/79) (10/27)
Partial.......... 65.2.. 75.0.....86.4....75.3.. 8.7
Responders SVR24.(15/23) (18/24) (19/22) (52/69)(2/23)
Null...............52.9...41.2... 58.8....51.0...18.8
Responders SVR24...9/17) (7/17) (10/17) (26/51) (3/16)
q.d.: once daily; PR: pegIFNalpha-2A and ribavirin; EoT: End of Treatment, SVR24: patients with undetectable HCV RNA (<25 IU/mL Undetectable) 24 weeks after planned EoT. All TMC435 groups: p<0.001 vs placebo. Prior Relapser: undetectable HCV RNA at EoT and detectable within 24 weeks of follow-up Prior Partial Responders: more than 2 log reduction in HCV RNA at W12 but not achieving undetectable at EoT Prior Null Responders: less than 2 log reduction in HCV RNA at W12
Results -- Safety and Tolerability TMC435 was generally safe and well tolerated and overall incidence of adverse events (AEs) was similar across treatment groups. Most of the AEs were grade 1 or 2 in severity. Serious AEs (SAEs) were reported in 6.1% subjects in the placebo and in 7.8% of the patients treated with TMC435. AEs leading to treatment discontinuation were reported in 4.5% of the placebo patients and in 7.8% of the TMC435 treated patients. Patients in the TMC435 ASPIRE treatment groups had overall longer treatment duration than patients in the placebo group due to a higher frequency of early discontinuation in the placebo group due to treatment failures (i.e. reaching viral stopping rules). The most common AEs during the treatment period were headache, fatigue, pruritus and influenza-like illness. Incidence was similar across treatment groups and the level of AEs and frequency were consistent with the prior phase IIb (PILLAR) study in treatment-naive hepatitis C patients of TMC435.
In the safety analyses, special attention was given to the following AEs of interest: hepatobiliary AEs, pruritus, rash and anemia. Most AEs of interest were grade 1 or 2 in severity and infrequently led to treatment discontinuation. For each category of AEs of interest the incidence was similar for the TMC435 treatment arms and control arm.
Mild and reversible increases in bilirubin (total, direct and indirect) were observed in TMC435 dose groups with no differences between 100 mg and 150 mg. There were no meaningful differences between treatment groups for any of the other laboratory parameters. There were no clinically significant findings on vital signs. Mean alanine aminotransferase (ALT) levels decreased in all treatment groups.
DRAGON (C215) -- Update on recently published results The final data from the phase II Dragon study in Japan was recently published at the Japan Digestive Disease Week meeting, 20-23 October 2011 in Fukuoka, Japan. The DRAGON study is a phase II randomized, open-label, response-guided study to evaluate the efficacy, safety, and pharmacokinetics of TMC435 plus PegIFN/RBV in 92 Japanese treatment-naive patients infected with HCV genotype-1.
Addition of once daily TMC435 (100 mg) to PegIFN/RBV increased the viral cure rate (SVR24) from 46% in the PegIFN/RBV only group to 82% (32/39) in the TMC435 100mg groups. In these groups, 87% of patients were eligible to complete all treatment at Week 24 if preset criteria on virologic response were met. TMC435 was generally safe and well tolerated with no apparent difference in the safety profile between TMC435 treatment groups and the control group (PegIFN/RBV only).
About TMC435 TMC435 is a highly potent and selective once-daily (q.d.) investigational drug that is being jointly developed by Tibotec Pharmaceuticals and Medivir to treat chronic hepatitis C virus infections.
TMC435 has received "Fast Track" designation by the U.S. Food and Drug Administration ("FDA") for the treatment of chronic hepatitis C (CHC) genotype-1 infection. This is based on TMC435's potential to address unmet medical needs in the treatment of chronic HCV infection. TMC435 is currently being developed in three global phase III studies, QUEST-1 and QUEST-2 in treatment-naive patients and PROMISE in patients who have relapsed after prior interferon-based treatment. In parallel with these trials, phase III studies for TMC435 in Japan, in both treatment naive and treatment experienced hepatitis C genotype-1 infected patients, are ongoing.
For additional information from these studies, please see www.medivir.com and www.clinicaltrials.gov
Conference call for analysts and investors: There will be a conference call today, 2 November 2011, for investors and analysts at 11.00 (EDT) / 15.00 (GMT) / 16.00 (CET) to discuss the data. To dial-in to the conference call please use the following numbers:
Participant telephone numbers: Sweden +46 (0)200 884 518 Europe +44 (0)1452 569 335 USA +1 866 655 1591 Please quote participant code 23849230
Soundbyte replay access numbers: Sweden +46 (0)200 899 157 Europe +44 (0)1452 55 00 00 USA +1 866 247 4222 Replay access code: 23849230#
About Hepatitis C Hepatitis C is a blood-borne infectious disease of the liver and is a leading cause of chronic liver disease and liver transplants. The WHO estimates that nearly 180 million people worldwide, or approximately 3% of the world's population, are infected with hepatitis C virus (HCV). The CDC has reported that almost three million people in the United States are chronically infected with HCV.
About Medivir Medivir is an emerging research-based specialty pharmaceutical company focused on the development of high-value treatments for infectious diseases. Medivir has world class expertise in polymerase and protease drug targets and drug development which has resulted in a strong infectious disease R&D portfolio. The Company's key pipeline asset is TMC435, a novel protease inhibitor that is in phase III clinical development for hepatitis C and is partnered with Tibotec Pharmaceuticals.
In June 2011, Medivir acquired the specialty pharmaceutical company BioPhausia to ensure timely commercialization of TMC435 in the Nordic markets, once approved.
Medivir's first product, the unique cold sore product Xerese(R)/Xerclear(R), was launched on the US market in February 2011. Xerese(R)/Xerclear(R), which has been approved in both the US and Europe is partnered with GlaxoSmithKline to be sold OTC in Europe, Japan and Russia. Rights in North America, Canada and Mexico were sold to Meda AB in June 2011. Medivir has retained the Rx rights for Xerclear(R) in Sweden and Finland.
For more information about Medivir, please visit the Company's website: www.medivir.com .
Medivir
For more information about Medivir, please visit the Company's website: www.medivir.com ( http://www.medivir.com/ ).
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SOURCE: Medivir
Copyright Business Wire 2011
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