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Antiviral Appears to Improve HCV Treatment
By Michael Smith, North American Correspondent, MedPage Today
Published: April 29, 2009
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston. Earn CME/CE credit
for reading medical news
TORONTO, April 29 -- Adding an antiviral drug to standard hepatitis C therapy shortened the treatment time and increased response rates, two studies found.
Action Points
■Explain to interested patients that standard treatment for hepatitis C takes about 48 weeks and is associated with unpleasant side effects.
■Note that these studies suggest that adding an investigational antiviral drug to the mix shortens the treatment duration and increases the response time.
In the phase II studies, with slightly different designs, the investigational protease inhibitor telaprevir increased response rates by about 50%, the researchers reported in the April 30, 2009 issue of the New England Journal of Medicine.
The finding appears to be the first "material advance" in hepatitis C therapy since the introduction of pegylated interferon in 2001, according to Jay Hoofnagle, M.D., of the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Md.
Commenting on the studies in an accompanying editorial, Dr. Hoofnagle said the drug -- which inhibits a specific serine protease of the hepatitis C virus -- marks the "beginning (of) a new era of treatment -- an era of antiviral agents developed specifically to target this virus."
In the first of the two studies -- both sponsored by the drug's developer -- John McHutchison, M.D., of Duke University, and colleagues randomized 250 patients with genotype 1 hepatitis C to one of four regimens.
The control group got standard therapy -- 48 weeks of ribavirin (Copegus, Rebetol) and peginterferon alfa-2a (Pegasys) -- and was compared with three other groups:
•79 patients who got telaprevir for 12 weeks and 24 weeks of the standard drugs
•79 patients who got 12 weeks of telaprevir and 48 weeks of standard therapy
•A small exploratory group of 17 patients who got telaprevir (1,250 milligrams on day one and 750 milligrams every eight hours thereafter) for 12 weeks, as well as peginterferon alfa-2a and ribavirin for the same 12 weeks
The primary outcome was sustained virologic response, defined as an undetectable level of hepatitis C RNA 24 weeks after the end of therapy.
The researchers reported that the sustained virologic response rate was 41% in the control group, compared with 61% in the patients who got 12 weeks of telaprevir and 24 weeks of the standard drugs, a difference that was significant at P=0.02.
The response rate was 67% in the patients who got 12 weeks of telaprevir and 48 weeks of the standard drugs, which was significant at P=0.002, compared with standard therapy.
In the exploratory group, which was not compared with the control group, the rate was 35%.
Standard treatment "cures less than half of patients and has significant side effects that make it very difficult for some patients to continue their treatment," Dr. McHutchison said in a statement.
"Our study found that by combining the standard therapy with the direct antiviral drug telaprevir, we could reduce the duration of treatment by 50%, to 24 weeks, and, at the same time, improve the cure rate by 50%."
One problem with telaprevir therapy was the incidence of adverse drug reactions -- primarily occurrence of rash -- which was higher than in the control group. This led to a higher rate of drug discontinuation than in the control group.
Results were similar in the second study, although the drug combinations analyzed were slightly different, according to Jean-Michel Pawlotsky, M.D., Ph.D., of the Henri Mondor Hospital in Paris, and colleagues.
The researchers compared outcomes in a control group of 82 patients who got standard therapy with outcomes among:
•81 patients who got telaprevir for 12 weeks and 24 weeks of the standard drugs
•82 patients who were treated with all three drugs for 12 weeks only
•78 patients who got telaprevir and peginterferon alfa-2a -- without ribavirin -- for 12 weeks
The rate of sustained virologic response for the control group was 46%, compared with 69% in the patients who got telaprevir and 24 weeks of peginterferon alfa-2a ribavirin. The difference was significant at P=0.004.
On the other hand, the rate in the other two telaprevir groups combined was not significantly different from that in the control group, the researchers found.
They concluded that ribavirin was a critical part of the treatment regimen.
The studies were supported by Vertex Pharmaceuticals.
Dr. McHutchison reported financial links with Vertex Pharmaceuticals, Schering-Plough, and Roche.
Dr. Pawlotsky reported financial links with Abbott, Astra-Zeneca, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Roche, Schering-Plough, Tibotec Pharmaceuticals, Valeant Pharmaceuticals, and Vertex Pharmaceuticals.
Dr. Hoofnagle reported no conflicts.
Primary source: New England Journal of Medicine
Source reference:
McHutchison JG, et al "Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection" N Engl J Med 2009; 360: 1827-38.
Additional source: New England Journal of Medicine
Source reference:
Hézode C, et al "Telaprevir and peginterferon with or without ribavirin for chronic HCV infection" N Engl J Med 2009; 360: 1839-50.
Additional source: New England Journal of Medicine
Source reference:
Hoofnagle, JH "A step forward in therapy for hepatitis C" N Engl J Med 2009; 360: 1899-1901
Thursday, April 30, 2009
Wednesday, April 29, 2009
New Hep B Vaccine
EASL Oral Presentations
Session Title: Parallel Session 11: LATE-BREAKERS
Presentation Date: Apr 25, 2009
A PHASE 3 SAFETY AND EFFICACY STUDY COMPARING IMMUNOGENICITY OF TWO DOSES OF HBSAG COMBINED WITH IMMUNOSTIMULATORY SEQUENCE WITH THREE DOSES OF LICENSED HEPATITIS VACCINE
M.L. Pecoraro1, J.T. Martin Sr.1, S. Halperin2, F. Diaz-Mitoma3
1Dynavax Technologies, Berkeley, CA, USA, 2Dalhousie University, Halifax, NS, 3Herridge Clinic, Ottawa, ON, Canada
The current licensed Hepatitis B virus (HBV) vaccines contain HBsAg adjuvanted with aluminum hydroxide and are administered in 3 doses over a 6 month period. HBsAg-ISS, a vaccine that contains a new class of adjuvant (1018 Immunostimulatory Sequence, or ISS), a Toll-like Receptor 9 (TLR9) agonist, has previously demonstrated 100% seroprotection after a short regimen of only 2 doses in adults 18-39 years of age.
The aim of this study was to compare the proportion of subjects who exhibit seroprotective immune response (SPR - anti-HBsAg antibodies ≥ 10 mIU/mL by Ortho ECi) after 2 doses of HBsAg-ISS administered at 0 and 1 month to the proportion of subjects who exhibit SPR after 3 doses of Engerix-B administered at 0, 1 and 6 months among adults 18 to 55 years of age.
Methods: This was a randomized, observer-blind study where the primary immunogenicity endpoint was SPR measured 2 months after the last dose of HBsAg-ISS and 1 month after the last dose of Engerix-B. The primary hypothesis was that the HBsAg-ISS vaccine was non-inferior to the licensed vaccine as defined as the lower bound of the 95% CI on the difference in SPR exceeding 0.1.
Results: 2428 subjects enrolled in this study. Subjects were randomized in a ratio of 3:1 to HBsAg-ISS (n=1820) and Engerix-B (n=608). Demographic characteristics were evenly distributed between the two arms. The number of subjects excluded from the per-protocol analysis was similar for the two vaccination groups (14% for HBsAg-ISS and 12% for the Engerix-B group); most exclusions from both groups were the result of having primary serology samples outside the visit window. The percentage of subjects exhibiting SPR at the primary endpoint was 95.1% for 2 doses of HBsAg-ISS and 81.1% for subjects receiving 3 doses of Engerix-B; the difference in SPR between the two groups was 13.8 % (95% CI, 10.5% and 17.5%) indicating non-inferiority of the HBsAg-ISS vaccine.
Conclusion: This study successfully demonstrated that a short, 2 dose regimen of HBsAg-ISS is non-inferior to the current 3 dose regimen of Engerix-B.
Dynavax Presents Additional Phase 3 Data for HEPLISAV(TM)Hepatitis B Vaccine at EASL Medical Conference
BERKELEY, Calif., Apr 27, 2009 (BUSINESS WIRE) -- Dynavax Technologies Corporation (Nasdaq:DVAX) today announced the oral presentation of additional Phase 3 clinical data for HEPLISAV(TM) hepatitis B vaccine in a session for late-breaking abstracts at the 44th Annual Meeting of the European Association for the Study of Liver Disease (EASL) in Copenhagen, Denmark. As previously reported, HEPLISAV met its primary endpoint in this Phase 3 trial and demonstrated the vaccine's potential to provide more rapid and increased protection against hepatitis B viral infection and with fewer doses than the licensed vaccine.
This Phase 3 trial referred to as PHAST (Phase 3 HeplisAv Short-regimen Trial) evaluated more than 2,400 adults. The seroprotection rate at the primary endpoint was 95% in subjects receiving 2 doses of HEPLISAV at 0 and 1 month, compared to 81% in subjects receiving 3 doses of licensed vaccine Engerix-B(R) at 0, 1, and 6 months. At each time point, there was a statistically significant (p < 0.0001) difference in the seroprotection rate for subjects receiving HEPLISAV or Engerix-B.
TreatmentGroup
DosingRegimen
Seroprotection Rate (1)
at Month
1 2 3 6 7
HEPLISAV 2 doses (0, 1 month) 24% 89% 95%(2) 98% 98%
Engerix-B 3 doses (0, 1, 6 months) 4% 26% 23% 32% 81%(2)
(1) Seroprotection rate - percentage of subjects with anti-HBsAg antibodies â%¥ 10 mlU/mL
(2) Primary endpoint
As previously reported, safety results from this trial demonstrated the safety profile of HEPLISAV and Engerix-B appeared similar. Subjects were randomized 3 to 1 to receive HEPLISAV or Engerix-B and one case of vasculitis was reported in each of the treatment groups. Following the report of the severe adverse event of Wegener's granulomatosis, an uncommon form of vasculitis, HEPLISAV was placed and remains on clinical hold by the U.S. Food and Drug Administration. Dynavax is clarifying the remaining regulatory requirements for the potential development and licensure of HEPLISAV in the United States and Europe.
A copy of the presentation is available at http://investors.dynavax.com/events.cfm. Dynavax's abstract #587659 was titled "A Phase 3 Safety and Efficacy Study Comparing Immunogenicity of Two Doses of Hepatitis B Surface Antigen Combined with Immunostimulatory Sequence with Three Doses of Licensed Hepatitis Vaccine."
About HEPLISAV
HEPLISAV is a Phase 3 hepatitis B vaccine aimed at unmet medical needs in the vaccination of adults and end-stage renal disease patients by providing rapid and increased protection with fewer doses. HEPLISAV combines Dynavax's proprietary immunostimulatory sequences (ISS), which target Toll-like Receptor 9, with hepatitis B surface antigen (HBsAg). HEPLISAV targets an estimated $500 million global market opportunity for adult hepatitis B vaccines.
About Hepatitis B
Hepatitis B is a chronic disease which can lead to cirrhosis of the liver and hepatocellular carcinoma. There is no cure for hepatitis B and disease prevention through effective vaccines is critical to reducing the spread of the disease. Current hepatitis B vaccines for adults usually require 3 doses given over 6 months to provide seroprotection of approximately 30%, 75%, and 90% after the first, second, and third doses respectively. The effectiveness of current vaccines is further compromised because only 30% of people receive all 3 doses.
About Dynavax
Dynavax Technologies Corporation, a clinical-stage biopharmaceutical company, discovers and develops a diversified pipeline of novel Toll-like Receptor (TLR) based product candidates. Based on Dynavax's proprietary technologies, these products specifically modify the innate immune response to infectious, respiratory, autoimmune, and inflammatory diseases. Dynavax has partnerships with leading pharmaceutical companies such as GlaxoSmithKline, AstraZeneca, and Novartis as well as funding from Symphony Dynamo, Inc. and the National Institutes of Health. For more information visit www.dynavax.com.
Forward Looking Statements
This press release contains "forward-looking statements," that are subject to a number of risks and uncertainties, including statements related to the nature and timing of communications with regulatory agencies regarding HEPLISAV. Actual results may differ materially from those set forth in this press release due to the risks and uncertainties inherent in our business, including whether the provision of additional information requested by the FDA is found to be satisfactory to remove the clinical hold for HEPLISAV, whether HEPLISAV can be further developed, or even if further development is permitted, that successful clinical development and regulatory approval can occur in a timely manner or without significant additional studies and difficulties or delays in development; and other risks detailed in the "Risk Factors" section of our Annual Report on Form 10-K. We undertake no obligation to revise or update information herein to reflect events or circumstances in the future, even if new information becomes available.
Engerix-B(R) is a registered trademark of GlaxoSmithKline
SOURCE: Dynavax Technologies Corporation
Dynavax Technologies Corporation
Amy Figueroa, 510-665-7211
Investor Relations and Corporate Communications
afigueroa@dynavax.com
Session Title: Parallel Session 11: LATE-BREAKERS
Presentation Date: Apr 25, 2009
A PHASE 3 SAFETY AND EFFICACY STUDY COMPARING IMMUNOGENICITY OF TWO DOSES OF HBSAG COMBINED WITH IMMUNOSTIMULATORY SEQUENCE WITH THREE DOSES OF LICENSED HEPATITIS VACCINE
M.L. Pecoraro1, J.T. Martin Sr.1, S. Halperin2, F. Diaz-Mitoma3
1Dynavax Technologies, Berkeley, CA, USA, 2Dalhousie University, Halifax, NS, 3Herridge Clinic, Ottawa, ON, Canada
The current licensed Hepatitis B virus (HBV) vaccines contain HBsAg adjuvanted with aluminum hydroxide and are administered in 3 doses over a 6 month period. HBsAg-ISS, a vaccine that contains a new class of adjuvant (1018 Immunostimulatory Sequence, or ISS), a Toll-like Receptor 9 (TLR9) agonist, has previously demonstrated 100% seroprotection after a short regimen of only 2 doses in adults 18-39 years of age.
The aim of this study was to compare the proportion of subjects who exhibit seroprotective immune response (SPR - anti-HBsAg antibodies ≥ 10 mIU/mL by Ortho ECi) after 2 doses of HBsAg-ISS administered at 0 and 1 month to the proportion of subjects who exhibit SPR after 3 doses of Engerix-B administered at 0, 1 and 6 months among adults 18 to 55 years of age.
Methods: This was a randomized, observer-blind study where the primary immunogenicity endpoint was SPR measured 2 months after the last dose of HBsAg-ISS and 1 month after the last dose of Engerix-B. The primary hypothesis was that the HBsAg-ISS vaccine was non-inferior to the licensed vaccine as defined as the lower bound of the 95% CI on the difference in SPR exceeding 0.1.
Results: 2428 subjects enrolled in this study. Subjects were randomized in a ratio of 3:1 to HBsAg-ISS (n=1820) and Engerix-B (n=608). Demographic characteristics were evenly distributed between the two arms. The number of subjects excluded from the per-protocol analysis was similar for the two vaccination groups (14% for HBsAg-ISS and 12% for the Engerix-B group); most exclusions from both groups were the result of having primary serology samples outside the visit window. The percentage of subjects exhibiting SPR at the primary endpoint was 95.1% for 2 doses of HBsAg-ISS and 81.1% for subjects receiving 3 doses of Engerix-B; the difference in SPR between the two groups was 13.8 % (95% CI, 10.5% and 17.5%) indicating non-inferiority of the HBsAg-ISS vaccine.
Conclusion: This study successfully demonstrated that a short, 2 dose regimen of HBsAg-ISS is non-inferior to the current 3 dose regimen of Engerix-B.
Dynavax Presents Additional Phase 3 Data for HEPLISAV(TM)Hepatitis B Vaccine at EASL Medical Conference
BERKELEY, Calif., Apr 27, 2009 (BUSINESS WIRE) -- Dynavax Technologies Corporation (Nasdaq:DVAX) today announced the oral presentation of additional Phase 3 clinical data for HEPLISAV(TM) hepatitis B vaccine in a session for late-breaking abstracts at the 44th Annual Meeting of the European Association for the Study of Liver Disease (EASL) in Copenhagen, Denmark. As previously reported, HEPLISAV met its primary endpoint in this Phase 3 trial and demonstrated the vaccine's potential to provide more rapid and increased protection against hepatitis B viral infection and with fewer doses than the licensed vaccine.
This Phase 3 trial referred to as PHAST (Phase 3 HeplisAv Short-regimen Trial) evaluated more than 2,400 adults. The seroprotection rate at the primary endpoint was 95% in subjects receiving 2 doses of HEPLISAV at 0 and 1 month, compared to 81% in subjects receiving 3 doses of licensed vaccine Engerix-B(R) at 0, 1, and 6 months. At each time point, there was a statistically significant (p < 0.0001) difference in the seroprotection rate for subjects receiving HEPLISAV or Engerix-B.
TreatmentGroup
DosingRegimen
Seroprotection Rate (1)
at Month
1 2 3 6 7
HEPLISAV 2 doses (0, 1 month) 24% 89% 95%(2) 98% 98%
Engerix-B 3 doses (0, 1, 6 months) 4% 26% 23% 32% 81%(2)
(1) Seroprotection rate - percentage of subjects with anti-HBsAg antibodies â%¥ 10 mlU/mL
(2) Primary endpoint
As previously reported, safety results from this trial demonstrated the safety profile of HEPLISAV and Engerix-B appeared similar. Subjects were randomized 3 to 1 to receive HEPLISAV or Engerix-B and one case of vasculitis was reported in each of the treatment groups. Following the report of the severe adverse event of Wegener's granulomatosis, an uncommon form of vasculitis, HEPLISAV was placed and remains on clinical hold by the U.S. Food and Drug Administration. Dynavax is clarifying the remaining regulatory requirements for the potential development and licensure of HEPLISAV in the United States and Europe.
A copy of the presentation is available at http://investors.dynavax.com/events.cfm. Dynavax's abstract #587659 was titled "A Phase 3 Safety and Efficacy Study Comparing Immunogenicity of Two Doses of Hepatitis B Surface Antigen Combined with Immunostimulatory Sequence with Three Doses of Licensed Hepatitis Vaccine."
About HEPLISAV
HEPLISAV is a Phase 3 hepatitis B vaccine aimed at unmet medical needs in the vaccination of adults and end-stage renal disease patients by providing rapid and increased protection with fewer doses. HEPLISAV combines Dynavax's proprietary immunostimulatory sequences (ISS), which target Toll-like Receptor 9, with hepatitis B surface antigen (HBsAg). HEPLISAV targets an estimated $500 million global market opportunity for adult hepatitis B vaccines.
About Hepatitis B
Hepatitis B is a chronic disease which can lead to cirrhosis of the liver and hepatocellular carcinoma. There is no cure for hepatitis B and disease prevention through effective vaccines is critical to reducing the spread of the disease. Current hepatitis B vaccines for adults usually require 3 doses given over 6 months to provide seroprotection of approximately 30%, 75%, and 90% after the first, second, and third doses respectively. The effectiveness of current vaccines is further compromised because only 30% of people receive all 3 doses.
About Dynavax
Dynavax Technologies Corporation, a clinical-stage biopharmaceutical company, discovers and develops a diversified pipeline of novel Toll-like Receptor (TLR) based product candidates. Based on Dynavax's proprietary technologies, these products specifically modify the innate immune response to infectious, respiratory, autoimmune, and inflammatory diseases. Dynavax has partnerships with leading pharmaceutical companies such as GlaxoSmithKline, AstraZeneca, and Novartis as well as funding from Symphony Dynamo, Inc. and the National Institutes of Health. For more information visit www.dynavax.com.
Forward Looking Statements
This press release contains "forward-looking statements," that are subject to a number of risks and uncertainties, including statements related to the nature and timing of communications with regulatory agencies regarding HEPLISAV. Actual results may differ materially from those set forth in this press release due to the risks and uncertainties inherent in our business, including whether the provision of additional information requested by the FDA is found to be satisfactory to remove the clinical hold for HEPLISAV, whether HEPLISAV can be further developed, or even if further development is permitted, that successful clinical development and regulatory approval can occur in a timely manner or without significant additional studies and difficulties or delays in development; and other risks detailed in the "Risk Factors" section of our Annual Report on Form 10-K. We undertake no obligation to revise or update information herein to reflect events or circumstances in the future, even if new information becomes available.
Engerix-B(R) is a registered trademark of GlaxoSmithKline
SOURCE: Dynavax Technologies Corporation
Dynavax Technologies Corporation
Amy Figueroa, 510-665-7211
Investor Relations and Corporate Communications
afigueroa@dynavax.com
New Protease Inhibitors
There were so many new drugs for HCV presented at EASL, there are about 7 protease inhibitors and 10 polymerase inhibitors being studied now in patients at various stages of develoment. Some of the polymerase inhibitors will be able to be combined. A NRTI like R7128, the Rocjhe/Pharmasset drug, can be combined with a NNRTI, but also some NNRTI can be combined because they bind at different sites. So what that means is that if a patient took a protease regimen and failed and got resistance we hope and expect other types of regimens might work. Several protease inhibitor might be effective against telaprevir and boceprevir resistance but its way to early to know and I suggest not counting on this. But the Enata/Abbott protease and the new Schering protease are able to achieve high blood levels and perhaps they might suppress resistance virus like Kaletra could suppress saquinavir resistance for some patients. Researchers are in very early stages of trying to develop a second generation protease that might effectively suppress resistant virus from telaprevir, but I prefer to be cautious if I can have that luxury. So the SVR rates with telaprevir in phase 2 are 65% in genotype naives but 39% in prior nonresponders but they don't break out the SVR rates for null responders so if they could it would be less than 39%. We expect to get data in null responders from their phase 3 studies. This means if you can wait for better therapy you might want to. The INFORM Study conducted by Roche with Pharmasset & Intermune showed at EASL the results of combining 2 oral drugs, their 2 orals the protease ITMN191/R7227 + R7128 the NRTI. The potency was very good, additive. In monotherapy ITMN191 gives a 4 log drop and R7128 about 2.7 logs. Roche is rushing ahead in the next set of studies. So 2 orals + Peg/RBV is on the horizon and will be more potent than one protease + peg/RBV especially for prior nonresponders. At some point we will have combinations of 3 or more orals with peg/RBV and then we can expect 80-90% SVR rates for all patients including African-Americans, I think. Of course the companies are planning to conduct studies to see if they can get rid of peg/RBV and we will see if thats possible. One eminent researcher, Eugene Schiff from the University of Miami, told me he is very confident that within 5 years we will have regimens without peg/RBV, I am not as sure but we will see. Right below here is a link to the first study in patients at a conference, reported at EASL, for the peginterferon that BMS recently bought. This IFN promises to have not to have the major side effects associated with interferon, this is an early study so more studies have to be conducted, but this study showed potency, take a look. In sum, HCV drug resistance is an important concern, resistance to a protease monotherapy can develop within a few days and adding peg/RBV reduces the risk a lot which is why we see 65% SVR rates with those 3 drugs, but there is a risk particularly for nonresponders and moreo for null responders to prior IFN. When making treatment decisions bear this in mind
Jules Levin NATAP
Jules Levin NATAP
Seabird
Seabird
I remember the day that I fell down on the shore, where I had so often gone to visit with my dreams of what would be But not this day, for I was too broken to ever want to rise again I just wanted to die quietly and gain some kind of release from those unrelenting torments of my shattered hopes and dreams I could even feel the numbness
begin to beckon me to sleep, perhaps to dream again Not that it mattered so much to me anymore But then something caught my eye, a darting movement down the shore just a few feet away from where I lay And in spite of my cold indifference, I became entranced by what I saw There was a little Seabird running back and forth in the surf, dueling with the waves which were rushing in and threatening to engulf it The Seabird seemed so tiny and fragile against these mighty fingers of the ocean, but it never once failed to rush into harm's way in a dedicated search for what it was seeking Surprising myself, I began to admire its courage and determination while I silently began to root for it I was never sure whether or not it actually found what it was after, but somewhere in this silent vigil I found what was missing in me As I finally rose to my knees with tears of understanding streaming down my cheeks, I thanked God for sending this sign of his love and compassion to a pilgrim who had lost his sight, perspective, and faith for a time
Dennis J Hopkins
09/2002
I remember the day that I fell down on the shore, where I had so often gone to visit with my dreams of what would be But not this day, for I was too broken to ever want to rise again I just wanted to die quietly and gain some kind of release from those unrelenting torments of my shattered hopes and dreams I could even feel the numbness
begin to beckon me to sleep, perhaps to dream again Not that it mattered so much to me anymore But then something caught my eye, a darting movement down the shore just a few feet away from where I lay And in spite of my cold indifference, I became entranced by what I saw There was a little Seabird running back and forth in the surf, dueling with the waves which were rushing in and threatening to engulf it The Seabird seemed so tiny and fragile against these mighty fingers of the ocean, but it never once failed to rush into harm's way in a dedicated search for what it was seeking Surprising myself, I began to admire its courage and determination while I silently began to root for it I was never sure whether or not it actually found what it was after, but somewhere in this silent vigil I found what was missing in me As I finally rose to my knees with tears of understanding streaming down my cheeks, I thanked God for sending this sign of his love and compassion to a pilgrim who had lost his sight, perspective, and faith for a time
Dennis J Hopkins
09/2002
Tuesday, April 28, 2009
Final Results SVR 24 Boceprevir plus PegIFN a-2b/Ribavirin
HCV SPRINT-1
Final Results SVR 24
Boceprevir plus PegIFN a-2b/Ribavirin
HCV Genotype 1 Treatment Naive Patients
EASL April 23-26, 2009 Copenhagen, Denmark
Reported by Jules Levin
P. Kwo1, E. Lawitz2, J. McCone3, E. Schiff4, J. Vierling5, D. Pound6, M. Davis7, J. Galati8, S. Gordon9, N. Ravendhran10, L. Rossaro11, F. Anderson12, I. Jacobson13, R. Rubin14, K. Koury15, C. Brass15, E. Chaudhri15, J. Albrecht15
1Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 2Alamo Medical Research, San Antonio, TX, 3Mount Vernon Endoscopy Center, Alexandria, VA, 4Center for Liver Diseases, University of Miami Miller School of Medicine, Miami, FL, 5Professor of Medicine and Surgery, Baylor College of Medicine, Houston, TX, 6Indianapolis Gastroenterology Research Foundation, Indianapolis, IN, 7Digestive Care/South Florida Center of Gastroenterology, Wellington, FL, 8Liver Specialists of Texas, Houston, TX, 9Department of Hepatology, Henry Ford Health Systems, Detroit, MI, 10Digestive Disease Associates, Baltimore, MD, 11Internal Medicine, University of California-Davis Medical Center, Sacramento, CA, USA, 12The Liver & Intestinal Research Center, Vancouver, BC, Canada, 13Weill Cornell Medical College, New York, NY, 14Digestive Healthcare of Georgia, Atlanta, GA, 15Schering-Plough Research Institute, Kenilworth, NJ, USA
AIMS OF THE STUDY
Evaluate safety/efficacy of PegIFN alfa-2b (PegIntron) 1.5 ug/kg plus RBV in combination with boceprevir
Assess impact on SVR
--RVR and EVR
--Effect of the 4-week lead-in of Peg/RBV which allows:
Achievement of steady state drug levels
Alpha interferon-mediated immune system activation
Lower HCV burden
Potentially decreased pool of pre-existing viral quasi-species
--24 vs 48 week treatment duration
--decreased ribavirin from 800-1400 mg/day to 400-1000 mg/day (the low dose was explored to see the affect on anemia)
SVR
LINK TO SEE SOME BUT NOT ALL SLIDES:
Schering's protease boceprevir phase 2; Schering symposium - (04/27/09)
Peg/RBV Control group 48 weeks (=104): 38% SVR (But, 86% with EVR (32/37) had SVR; 8/8 with RVR had SVR)
Peg/RBV 28 weeks (n=107): 54% (74% of patients with RVR had SVR, 32/43; 68% with EVR had SVR, 58/85)
Peg/RBV 4 weeks - then P/R/B 24 weeks (n=103): 56% (82% with RVR had SVR, 54/68; 68% with EVR had SVR, 58/85)
P/R/B 48 weeks (n=103): 67% (84% wit RVR had SVR, 32/38; 84% with EVR had SVR, 68/81)
P/R 4 weeks then P/R/B 44 weeks (n=105): 75% (94% with RVR achieved SVR, 62/68; 91% with EVR achieved SVR, 77/85)
WHEN USING LOW-DOSE RBV:
Peg/RBV 48 weeks (n=50) Overall SVR: 36% comparable to control arm
P/R/B 48 weeks (n=16): 50%
PREDICTABILITY OF SVR: RVR and EVR
RVR
- 8 patients in the control group Peg/RBV achieved RVR and all went on to SVR (100%)
- 82% of patients with 4-week P/R lead-in and 24 weeks P/R/B who had RVR achieved SVR
- 94% of patients with 4 week P/R lead-in and 44 weeks P/R/B achieved SVR
EVR
- 86% of patients (n=37) who achieved EVR went on to SVR in the Peg/RBV control group
- 68% of patients receiving 4 week lead-in followed by 24 weeks P/R/B who had EVR achieved SVR
- 91% of patients receiving 4 week Peg/RBV lead-in followed by 44 weeks P/R/B who achieved EVR went on to SVR
Kwo then showed a chart called Effect of Treatment Duration on SVR.
- If time to 1st PCR-neg was 4 or less weeks 8/8 in control 48 wks, 54/66 (82%) in PR4/PRB 24 wks, and 62/66 94% had SVR.
- If time to SVR was 4-12 weeks 24/29 83% in PR control 48 wks, 4/19 21% in PRB 24 wks, and 15/19 79% in PR4/PRB 44 wks had SVR, and Kwo said extending treatment in this group led to better response. Why is this different in the group above under PREDICTABILITY, is it 12 wks EVR vs between 4-12?
Kwo then showed an interesting table where SVR predictability was based on response during 4 week lead-in Peg/RBV. For patients with <0.5 log reduction, essentially null responders, 2/7 (29%) in PR 4 wks/PRB 24 wks had SVR, and 44% (4/9) in PR 4 wks/PRB 44 wks had SVR. The numbers of patients are small but the suggestion is that 44% of null responders achieved SVR in this group.
In the patients with 0.5-1.0 log reduction 24% (5/21) in the 4 wk leadin/24 wk PRB group and 62% (8/13) in the 4 wk leadin/44 wks PRB group had SVR thus again suggesting that poor responders to Peg/RBV might achieve good SVR rate. For patients with 1 to 1.5 logs reduction, 30% (3/10) and 65% (11/17) had SVR in the 24 & 44 wk groups after leadin, respectively
Patients with 1.5-2.0 logs viral load reduction in leadin- 73% (8/11) in 24 week group and 80% in 44 week group had SVR.
Patients with 2-3 log reduction in leadin - 67% (14/21) & 79% (11/14) had SVR.
Patients with 3-4 log reduction in leadin - 83% (10/12) & 82% (14/17) had SVR.
Patients with >4 logs - 100% (11/11) had SVR in 24 week group & 92% (11/12) in 44 week group had SVR.
Patients who achieved undetectable in leadin: 100% (3/3) in 24 wk & 100% (9/9) in 44 wk groups had SVR.
Kwo presented a table showing patients with anemia had better SVR rates: 88% vs 64% for patients in 4 wk P/R leadin/44 wks P/R/B; 67% vs 47% for patients with 4 wk leadin/24 weeks P/R/B; and for patients in control group 48% vs 35%.
RELAPSE
Kwo reported 24% relapse rates in P/R control 48 weeks similar to that seen in IDEAL he said and similarly 30% and 24% in the 24 wk group and in the 4 week leadin/24 week PRB group. But 7% in the P/R/B 44 wk group & 3% in the PR 4 wk leadin/44 wks P/R.B group. Patients in each group who achieved RVR had lower relapse rates.
ANEMIA
34% on patients in 48 week peg/rbv control group had anemia
And I couldn't read the chart very well but 50-60% in the other 24 and 48 week regimens.
And 24% in the low dose 48 wk RBV group.
EPO USE
26% in the control group used EPO and 50% in the 2 leadin groups both 24 & 44 wks used EPO. Of note EPO use reduced discontinuations quite a lot; in the 24 week with lead in the discontinuation rate was 38% without EPO vs 14% with EPO, and in the 4 wk lead with 44 weeks it was reduced by 50%. The authors summarized "no beceprevir defining toxiity responsible for treatment discontinuation; boceprevir is associated with additional approximate 1 g/dL incremental hemoglobin decrease; anemia management with EPO is associated with increased completion rates.
VIRAL BREAKTHROUGHS
were lower in the leadin groups 7% for PRB 24 weeks vs 4% with leadin; 12% for PRB 48 wks vs 5% with leadin, and 25% with low dose RBV group.
MUTATIONS
Major mutations (>25%): V36M, T54S, R155K
Less common (>5% to <25%): T54A, V55A, R1555T, A156S, V158I, V170A
Infrequent (<5%): V36A, V36L, I170T
Final Results SVR 24
Boceprevir plus PegIFN a-2b/Ribavirin
HCV Genotype 1 Treatment Naive Patients
EASL April 23-26, 2009 Copenhagen, Denmark
Reported by Jules Levin
P. Kwo1, E. Lawitz2, J. McCone3, E. Schiff4, J. Vierling5, D. Pound6, M. Davis7, J. Galati8, S. Gordon9, N. Ravendhran10, L. Rossaro11, F. Anderson12, I. Jacobson13, R. Rubin14, K. Koury15, C. Brass15, E. Chaudhri15, J. Albrecht15
1Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 2Alamo Medical Research, San Antonio, TX, 3Mount Vernon Endoscopy Center, Alexandria, VA, 4Center for Liver Diseases, University of Miami Miller School of Medicine, Miami, FL, 5Professor of Medicine and Surgery, Baylor College of Medicine, Houston, TX, 6Indianapolis Gastroenterology Research Foundation, Indianapolis, IN, 7Digestive Care/South Florida Center of Gastroenterology, Wellington, FL, 8Liver Specialists of Texas, Houston, TX, 9Department of Hepatology, Henry Ford Health Systems, Detroit, MI, 10Digestive Disease Associates, Baltimore, MD, 11Internal Medicine, University of California-Davis Medical Center, Sacramento, CA, USA, 12The Liver & Intestinal Research Center, Vancouver, BC, Canada, 13Weill Cornell Medical College, New York, NY, 14Digestive Healthcare of Georgia, Atlanta, GA, 15Schering-Plough Research Institute, Kenilworth, NJ, USA
AIMS OF THE STUDY
Evaluate safety/efficacy of PegIFN alfa-2b (PegIntron) 1.5 ug/kg plus RBV in combination with boceprevir
Assess impact on SVR
--RVR and EVR
--Effect of the 4-week lead-in of Peg/RBV which allows:
Achievement of steady state drug levels
Alpha interferon-mediated immune system activation
Lower HCV burden
Potentially decreased pool of pre-existing viral quasi-species
--24 vs 48 week treatment duration
--decreased ribavirin from 800-1400 mg/day to 400-1000 mg/day (the low dose was explored to see the affect on anemia)
SVR
LINK TO SEE SOME BUT NOT ALL SLIDES:
Schering's protease boceprevir phase 2; Schering symposium - (04/27/09)
Peg/RBV Control group 48 weeks (=104): 38% SVR (But, 86% with EVR (32/37) had SVR; 8/8 with RVR had SVR)
Peg/RBV 28 weeks (n=107): 54% (74% of patients with RVR had SVR, 32/43; 68% with EVR had SVR, 58/85)
Peg/RBV 4 weeks - then P/R/B 24 weeks (n=103): 56% (82% with RVR had SVR, 54/68; 68% with EVR had SVR, 58/85)
P/R/B 48 weeks (n=103): 67% (84% wit RVR had SVR, 32/38; 84% with EVR had SVR, 68/81)
P/R 4 weeks then P/R/B 44 weeks (n=105): 75% (94% with RVR achieved SVR, 62/68; 91% with EVR achieved SVR, 77/85)
WHEN USING LOW-DOSE RBV:
Peg/RBV 48 weeks (n=50) Overall SVR: 36% comparable to control arm
P/R/B 48 weeks (n=16): 50%
PREDICTABILITY OF SVR: RVR and EVR
RVR
- 8 patients in the control group Peg/RBV achieved RVR and all went on to SVR (100%)
- 82% of patients with 4-week P/R lead-in and 24 weeks P/R/B who had RVR achieved SVR
- 94% of patients with 4 week P/R lead-in and 44 weeks P/R/B achieved SVR
EVR
- 86% of patients (n=37) who achieved EVR went on to SVR in the Peg/RBV control group
- 68% of patients receiving 4 week lead-in followed by 24 weeks P/R/B who had EVR achieved SVR
- 91% of patients receiving 4 week Peg/RBV lead-in followed by 44 weeks P/R/B who achieved EVR went on to SVR
Kwo then showed a chart called Effect of Treatment Duration on SVR.
- If time to 1st PCR-neg was 4 or less weeks 8/8 in control 48 wks, 54/66 (82%) in PR4/PRB 24 wks, and 62/66 94% had SVR.
- If time to SVR was 4-12 weeks 24/29 83% in PR control 48 wks, 4/19 21% in PRB 24 wks, and 15/19 79% in PR4/PRB 44 wks had SVR, and Kwo said extending treatment in this group led to better response. Why is this different in the group above under PREDICTABILITY, is it 12 wks EVR vs between 4-12?
Kwo then showed an interesting table where SVR predictability was based on response during 4 week lead-in Peg/RBV. For patients with <0.5 log reduction, essentially null responders, 2/7 (29%) in PR 4 wks/PRB 24 wks had SVR, and 44% (4/9) in PR 4 wks/PRB 44 wks had SVR. The numbers of patients are small but the suggestion is that 44% of null responders achieved SVR in this group.
In the patients with 0.5-1.0 log reduction 24% (5/21) in the 4 wk leadin/24 wk PRB group and 62% (8/13) in the 4 wk leadin/44 wks PRB group had SVR thus again suggesting that poor responders to Peg/RBV might achieve good SVR rate. For patients with 1 to 1.5 logs reduction, 30% (3/10) and 65% (11/17) had SVR in the 24 & 44 wk groups after leadin, respectively
Patients with 1.5-2.0 logs viral load reduction in leadin- 73% (8/11) in 24 week group and 80% in 44 week group had SVR.
Patients with 2-3 log reduction in leadin - 67% (14/21) & 79% (11/14) had SVR.
Patients with 3-4 log reduction in leadin - 83% (10/12) & 82% (14/17) had SVR.
Patients with >4 logs - 100% (11/11) had SVR in 24 week group & 92% (11/12) in 44 week group had SVR.
Patients who achieved undetectable in leadin: 100% (3/3) in 24 wk & 100% (9/9) in 44 wk groups had SVR.
Kwo presented a table showing patients with anemia had better SVR rates: 88% vs 64% for patients in 4 wk P/R leadin/44 wks P/R/B; 67% vs 47% for patients with 4 wk leadin/24 weeks P/R/B; and for patients in control group 48% vs 35%.
RELAPSE
Kwo reported 24% relapse rates in P/R control 48 weeks similar to that seen in IDEAL he said and similarly 30% and 24% in the 24 wk group and in the 4 week leadin/24 week PRB group. But 7% in the P/R/B 44 wk group & 3% in the PR 4 wk leadin/44 wks P/R.B group. Patients in each group who achieved RVR had lower relapse rates.
ANEMIA
34% on patients in 48 week peg/rbv control group had anemia
And I couldn't read the chart very well but 50-60% in the other 24 and 48 week regimens.
And 24% in the low dose 48 wk RBV group.
EPO USE
26% in the control group used EPO and 50% in the 2 leadin groups both 24 & 44 wks used EPO. Of note EPO use reduced discontinuations quite a lot; in the 24 week with lead in the discontinuation rate was 38% without EPO vs 14% with EPO, and in the 4 wk lead with 44 weeks it was reduced by 50%. The authors summarized "no beceprevir defining toxiity responsible for treatment discontinuation; boceprevir is associated with additional approximate 1 g/dL incremental hemoglobin decrease; anemia management with EPO is associated with increased completion rates.
VIRAL BREAKTHROUGHS
were lower in the leadin groups 7% for PRB 24 weeks vs 4% with leadin; 12% for PRB 48 wks vs 5% with leadin, and 25% with low dose RBV group.
MUTATIONS
Major mutations (>25%): V36M, T54S, R155K
Less common (>5% to <25%): T54A, V55A, R1555T, A156S, V158I, V170A
Infrequent (<5%): V36A, V36L, I170T
Safety, pharmacokinetics and antiviral effect of BI 207127
EASL 44th Annual Meeting
April 22-26, 2009
Copenhagen, Denmark Back
Safety, pharmacokinetics and antiviral effect of BI 207127, a novel HCV RNA polymerase inhibitor, after 5 days' oral treatment in patients with chronic hepatitis C
Reported by Jules Levin
EASL Copenhagen, April 23-26 2009
Boerhinger Ingelheim reported on their HCV protease inhibitor at AASLD Nov 2008 where they reported the drug showed about 4 log reductions viral load in early studies. Phase II is ongoing and results from that study should be reported soon. They say in this poster in conclusions below they are planning a combination study of these 2 oral HCV drugs. The future of HCV therapy is multiple oral drugs in combination with peg/rbv until a company can establish that a regimen of oral drugs alone will produce an SVR without peg/RBV, which all the companies are planning to study. I expect 2 oral drugs plus peg/RBV should produce 75% or higher SVR rates in treatment-naives an a little owe in African-Americans and prior null and nonresponders.
Dominique Larrey1, Yves Benhamou2, Ansgar W Lohse3, Christian Trepo4, Christian Molleken5, Jean-Pierre Bronowicki6, Keikawus Arasteh7, Marc Bourliere8, Markus Heim9, Jaime Enriquez10, Andreas Erhardt11,Jean-Pierre Zarski12, Reiner Wiest13, Tilman Gerlach14, Heiner Wedemeyer15, Thomas Berg16, Jerry Stern17, Katherine Wu17, Nasri Abdallah18, Gerhard Nehmiz19, Wulf Boecher19, Jurgen Steffgen19 for the BI 207127 study group
1INSERM 632-CIC Hopital Saint Eloi, Montpellier, 2Hopital La Pitie Salpetriere Paris, 3Universitatsklinikum Hamburg-Eppendorf Hamburg, 4Hopital Hotel Dieu Lyon, 5Universitatsklinik Bochum, 6Hopital de Brabois Nancy, 7Epimed GmbH Berlin, 8Hopital Saint Joseph Marseille, 9Universitatsspital Basel, 10Hospital de la Santa Creu I Sant Pau Barcelona,11Universitatsklinikum Dusseldorf, 12Hopital Michalon Grenoble, 13Klinikum der Universitat Regensburg, 14Kantonsspital St. Gallen, 15Medizinische Hochschule Hannover, 16Charite Berlin Campus Virchow-Klinikum Berlin; Boehringer Ingelheim 17Ridgefield CT, 18Reims and 19Biberach
AUTHOR CONCLUSIONS
BI 207127 is a potent inhibitor of viral replication in monotherapy, causing a steep decline of VL at 800 mg q8h in the first 24 hours (5/9 patients with >4 log10 VL reduction at Day 5, no VL breakthroughs)
BI 207127 was safe and overall well tolerated; the only drug-related SAE, a moderate erythema, was managed effectively. One mild transient rash did not require BI207127 dose reduction or discontinuation
The results from the present study demonstrate, that further clinical development of this promising direct antiviral in combination therapy with PegIFN/RBVis warranted
A 4-week combination study will initiate in late Q2/2009
ABSTRACT
Background: BI207127 is a potent and specific non-nucleoside inhibitor of the HCVRNA-dependent RNApolymerase in vitro.
Methods: In a double blinded, sequential group comparison, 48 male and female HCVgenotype-1 patients with minimal to mild liver fibrosis were randomized (9 active, 3 placebo per group) and treated with 100, 200, 400 or 800 mg BI207127 q8h over 5 days, given p.o. as experimental tablet. Afurther dose level with 1,200 mg is ongoing. All patients were followed for 10-14 days. Plasma HCVRNAvirus load (VL) was measured by Roche COBAS TaqMan assay.
Results: Mean age was 49.5 ± 10.2 years, BMI25.3 ± 3.0 kg/m2. 13/48 patients were naive for anti-HCVtherapy. Mean log10 VL (IU/mL) at baseline was 6.40. VL decreased by >1 log10 in 2/9, 6/9, 8/9 and 8/9 patients treated with 100, 200, 400 and 800 mg, respectively. No response was seen with placebo.
No breakthrough was observed during treatment.
In the 800 mg group, 5/9 patients showed a >4 log10 drop in VL, and the effect persisted at least 24 hours after the last drug intake.
Mean VL drops on day 5 were 0.6, 1.2, 1.9 and 3.1 log10 steps, respectively.
One SAE was reported for 800 mg, a moderate generalized erythema with facial involvement, which resolved within 2 days after discontinuation of BI207127 and after antihistaminic treatment. A further, mild localized rash was also reported on 800 mg. These 2 patients showed by far the highest PK exposures. All other AEs were rated "mild" or "moderate" and were not dose-related. Investigators judged tolerability as "good" in 42/48 patients. Laboratory parameters did not show any relevant changes from baseline.
Plasma drug levels exhibited supra-proportional pharmacokinetics from 400 mg on. The first phase of VL decline was correlated with the early BI207127 plasma exposure.
Conclusions: BI207127, given as monotherapy p.o., demonstrated reliable antiviral activity against HCVgenotype 1.
INTRODUCTION
Hepatitis C virus (HCV) genotype 1 (GT-1) is mostly prevalent in the USA and Europe, but is also significant in Asia and Australia. Chronic GT-1 infection is associated with a sustained virological response to standard treatment with pegylated interferon and ribavirin in less than 50% of patients. This limited response stresses the need for new and more potent antiviral treatments
BI 207127 is a reversible, orally bioavailable, non-nucleoside inhibitor of the HCV RNA-dependent RNApolymerase in vitro
BI 207127 exhibits potent and specific inhibition of the HCV RNA-dependent RNA polymerase in enzymatic and cell-based assays with EC50 values of 23 nM and 11 nM for GT-1a and GT-1b, respectively
The aims of this study were to assess safety, pharmacokinetics and the antiviral effect of BI 207127 in patients with chronic HCV infection of GT-1
METHODS
BI 207127 dosages
This phase 1b trial was a double blinded, sequential, dose-escalating group comparison, studying doses of 100 mg, 200 mg, 400 mg, 800 mg and 1,200 mg every 8 hours (q8h), given for 5 days orally (experimental tablet). At each dose level, patients were randomized either to BI207127 (n=9) or a matching placebo (n=3)
All patients were followed for 10-14 days
Results from the first four dose levels (100 to 800 mg q8h) are presented here- As of April 2009, the 1,200 mg q8h cohort is ongoing
Overview of key protocols
· HCV RNA was measured by Roche COBAS TaqMan assay with a lower limit of quantification of 25 IU/mL and a limit of detection of 10 IU/mL
· HCV genotype was determined by Inno-LIPA, confirmation of subtypes by NS5B sequencing is ongoing
· Plasma levels of BI 207127 were determined by HPLC-MS/MS
· Pharmacokinetic (PK) parameters were calculated using non-compartmental analysis
Patient criteria
· Patients with chronic HCV infection of GT-1 were enrolled, with the following characteristics
- 18-70 years of age
- either treatment-naÏ ve or non-responders to a previous standard course of pegylated interferon and ribavirin
- minimal to mild liver fibrosis
- plasma HCVRNAvirus load (VL) ≥100,000 IU/mL
· Exclusion criteria were
- co-infection with HIV or HBV
- concurrent liver disease other than HCV
- past treatment with any experimental HCVpolymerase inhibitor
- evidence of liver cirrhosis, active drug or alcohol abuse
- use of any comedication
- alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 x upper limit of normal (ULN)
- bilirubin >1.5 x ULN and not due to Gilbert's disease
- partial thromboplastin time (PTT) (International Normalized Ratio, INR) >1.5 x
ULN
- creatinine >1 x ULN
- white blood cell (WBC) count <2,000/mm3
- platelet count <100,000/mm3
-- haemoglobin <12 g/dL
RESULTS
Patient characteristics
· A total of 48 (male and female) HCV GT-1 patients were enrolled In the first four dose groups (100-800 mg q8h) (Table 1)
- Overall, 36 patients received BI207127, 12 patients received placebo
- 19/48 patients were naive for previous anti-HCV therapy
· The mean age of these 48 patients was 49.5 ± 10.2 years (n=48)
· The mean body mass index (BMI) was 25.3 ± 3.0 kg/m2 (n=48)
· At baseline the mean log10 VL was 6.40 IU/mL (n=48)
Pharmacokinetics
· Plasma drug levels exhibited supra-proportional pharmacokinetics at steady state with 400 mg and 800 mg doses (Figure 1)
· These data plus the PK profile from a single dose escalation study in healthy volunteers suggest that BI207127 may be suitable for three times a day dosing (instead of strict q8h) in the treatment of chronic HCV infection
Viral load
· The antiviral effect of BI 207127 was dose related
· VL decreases by ≥2 log10 were achieved in the majority of patients receiving doses of 400 mg or 800 mg q8h (Table 2)
· Mean (median) VL drops in the morning of Day 5 (log10 steps; Figure 2) were
- 0.6 (0.4) receiving 100 mg
- 1.1 (0.8) receiving 200 mg
- 1.9 (1.3) receiving 400 mg
- 3.1 (3.8) receiving 800 mg
· No response was seen with placebo
· No breakthrough was observed during treatment
· In the group receiving 800 mg, 5/9 patients showed a ≥4 log10 maximal drop in VL, 2/9 patients achieved VL <25 IU/mL
-- The antiviral effect persisted at least 24 hours after the last drug intake (Figure 3)
Safety profile
Overall AEs were rated mild or moderate and were not considered dose-related (Table 3)
Investigators judged tolerability of BI 207127 as good in 88% (n=32/36) of active-treated patients
Two cases of rash were reported, these two patients exhibited the highest PK exposures
- The only serious adverse event (SAE) related to the intake of BI207127 was a moderate generalized erythema with facial involvement. This patient was receiving 800 mg q8h and the SAE resolved within 2 days after discontinuation of BI207127 and after antihistaminic treatment
- Another patient reported rash (800 mg q8h) which was mild, localized and transient under continued treatment
Laboratory parameters did not show any relevant changes from baseline. There were no signs of liver, kidney or haematotoxicity (Table 4)
April 22-26, 2009
Copenhagen, Denmark Back
Safety, pharmacokinetics and antiviral effect of BI 207127, a novel HCV RNA polymerase inhibitor, after 5 days' oral treatment in patients with chronic hepatitis C
Reported by Jules Levin
EASL Copenhagen, April 23-26 2009
Boerhinger Ingelheim reported on their HCV protease inhibitor at AASLD Nov 2008 where they reported the drug showed about 4 log reductions viral load in early studies. Phase II is ongoing and results from that study should be reported soon. They say in this poster in conclusions below they are planning a combination study of these 2 oral HCV drugs. The future of HCV therapy is multiple oral drugs in combination with peg/rbv until a company can establish that a regimen of oral drugs alone will produce an SVR without peg/RBV, which all the companies are planning to study. I expect 2 oral drugs plus peg/RBV should produce 75% or higher SVR rates in treatment-naives an a little owe in African-Americans and prior null and nonresponders.
Dominique Larrey1, Yves Benhamou2, Ansgar W Lohse3, Christian Trepo4, Christian Molleken5, Jean-Pierre Bronowicki6, Keikawus Arasteh7, Marc Bourliere8, Markus Heim9, Jaime Enriquez10, Andreas Erhardt11,Jean-Pierre Zarski12, Reiner Wiest13, Tilman Gerlach14, Heiner Wedemeyer15, Thomas Berg16, Jerry Stern17, Katherine Wu17, Nasri Abdallah18, Gerhard Nehmiz19, Wulf Boecher19, Jurgen Steffgen19 for the BI 207127 study group
1INSERM 632-CIC Hopital Saint Eloi, Montpellier, 2Hopital La Pitie Salpetriere Paris, 3Universitatsklinikum Hamburg-Eppendorf Hamburg, 4Hopital Hotel Dieu Lyon, 5Universitatsklinik Bochum, 6Hopital de Brabois Nancy, 7Epimed GmbH Berlin, 8Hopital Saint Joseph Marseille, 9Universitatsspital Basel, 10Hospital de la Santa Creu I Sant Pau Barcelona,11Universitatsklinikum Dusseldorf, 12Hopital Michalon Grenoble, 13Klinikum der Universitat Regensburg, 14Kantonsspital St. Gallen, 15Medizinische Hochschule Hannover, 16Charite Berlin Campus Virchow-Klinikum Berlin; Boehringer Ingelheim 17Ridgefield CT, 18Reims and 19Biberach
AUTHOR CONCLUSIONS
BI 207127 is a potent inhibitor of viral replication in monotherapy, causing a steep decline of VL at 800 mg q8h in the first 24 hours (5/9 patients with >4 log10 VL reduction at Day 5, no VL breakthroughs)
BI 207127 was safe and overall well tolerated; the only drug-related SAE, a moderate erythema, was managed effectively. One mild transient rash did not require BI207127 dose reduction or discontinuation
The results from the present study demonstrate, that further clinical development of this promising direct antiviral in combination therapy with PegIFN/RBVis warranted
A 4-week combination study will initiate in late Q2/2009
ABSTRACT
Background: BI207127 is a potent and specific non-nucleoside inhibitor of the HCVRNA-dependent RNApolymerase in vitro.
Methods: In a double blinded, sequential group comparison, 48 male and female HCVgenotype-1 patients with minimal to mild liver fibrosis were randomized (9 active, 3 placebo per group) and treated with 100, 200, 400 or 800 mg BI207127 q8h over 5 days, given p.o. as experimental tablet. Afurther dose level with 1,200 mg is ongoing. All patients were followed for 10-14 days. Plasma HCVRNAvirus load (VL) was measured by Roche COBAS TaqMan assay.
Results: Mean age was 49.5 ± 10.2 years, BMI25.3 ± 3.0 kg/m2. 13/48 patients were naive for anti-HCVtherapy. Mean log10 VL (IU/mL) at baseline was 6.40. VL decreased by >1 log10 in 2/9, 6/9, 8/9 and 8/9 patients treated with 100, 200, 400 and 800 mg, respectively. No response was seen with placebo.
No breakthrough was observed during treatment.
In the 800 mg group, 5/9 patients showed a >4 log10 drop in VL, and the effect persisted at least 24 hours after the last drug intake.
Mean VL drops on day 5 were 0.6, 1.2, 1.9 and 3.1 log10 steps, respectively.
One SAE was reported for 800 mg, a moderate generalized erythema with facial involvement, which resolved within 2 days after discontinuation of BI207127 and after antihistaminic treatment. A further, mild localized rash was also reported on 800 mg. These 2 patients showed by far the highest PK exposures. All other AEs were rated "mild" or "moderate" and were not dose-related. Investigators judged tolerability as "good" in 42/48 patients. Laboratory parameters did not show any relevant changes from baseline.
Plasma drug levels exhibited supra-proportional pharmacokinetics from 400 mg on. The first phase of VL decline was correlated with the early BI207127 plasma exposure.
Conclusions: BI207127, given as monotherapy p.o., demonstrated reliable antiviral activity against HCVgenotype 1.
INTRODUCTION
Hepatitis C virus (HCV) genotype 1 (GT-1) is mostly prevalent in the USA and Europe, but is also significant in Asia and Australia. Chronic GT-1 infection is associated with a sustained virological response to standard treatment with pegylated interferon and ribavirin in less than 50% of patients. This limited response stresses the need for new and more potent antiviral treatments
BI 207127 is a reversible, orally bioavailable, non-nucleoside inhibitor of the HCV RNA-dependent RNApolymerase in vitro
BI 207127 exhibits potent and specific inhibition of the HCV RNA-dependent RNA polymerase in enzymatic and cell-based assays with EC50 values of 23 nM and 11 nM for GT-1a and GT-1b, respectively
The aims of this study were to assess safety, pharmacokinetics and the antiviral effect of BI 207127 in patients with chronic HCV infection of GT-1
METHODS
BI 207127 dosages
This phase 1b trial was a double blinded, sequential, dose-escalating group comparison, studying doses of 100 mg, 200 mg, 400 mg, 800 mg and 1,200 mg every 8 hours (q8h), given for 5 days orally (experimental tablet). At each dose level, patients were randomized either to BI207127 (n=9) or a matching placebo (n=3)
All patients were followed for 10-14 days
Results from the first four dose levels (100 to 800 mg q8h) are presented here- As of April 2009, the 1,200 mg q8h cohort is ongoing
Overview of key protocols
· HCV RNA was measured by Roche COBAS TaqMan assay with a lower limit of quantification of 25 IU/mL and a limit of detection of 10 IU/mL
· HCV genotype was determined by Inno-LIPA, confirmation of subtypes by NS5B sequencing is ongoing
· Plasma levels of BI 207127 were determined by HPLC-MS/MS
· Pharmacokinetic (PK) parameters were calculated using non-compartmental analysis
Patient criteria
· Patients with chronic HCV infection of GT-1 were enrolled, with the following characteristics
- 18-70 years of age
- either treatment-naÏ ve or non-responders to a previous standard course of pegylated interferon and ribavirin
- minimal to mild liver fibrosis
- plasma HCVRNAvirus load (VL) ≥100,000 IU/mL
· Exclusion criteria were
- co-infection with HIV or HBV
- concurrent liver disease other than HCV
- past treatment with any experimental HCVpolymerase inhibitor
- evidence of liver cirrhosis, active drug or alcohol abuse
- use of any comedication
- alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 x upper limit of normal (ULN)
- bilirubin >1.5 x ULN and not due to Gilbert's disease
- partial thromboplastin time (PTT) (International Normalized Ratio, INR) >1.5 x
ULN
- creatinine >1 x ULN
- white blood cell (WBC) count <2,000/mm3
- platelet count <100,000/mm3
-- haemoglobin <12 g/dL
RESULTS
Patient characteristics
· A total of 48 (male and female) HCV GT-1 patients were enrolled In the first four dose groups (100-800 mg q8h) (Table 1)
- Overall, 36 patients received BI207127, 12 patients received placebo
- 19/48 patients were naive for previous anti-HCV therapy
· The mean age of these 48 patients was 49.5 ± 10.2 years (n=48)
· The mean body mass index (BMI) was 25.3 ± 3.0 kg/m2 (n=48)
· At baseline the mean log10 VL was 6.40 IU/mL (n=48)
Pharmacokinetics
· Plasma drug levels exhibited supra-proportional pharmacokinetics at steady state with 400 mg and 800 mg doses (Figure 1)
· These data plus the PK profile from a single dose escalation study in healthy volunteers suggest that BI207127 may be suitable for three times a day dosing (instead of strict q8h) in the treatment of chronic HCV infection
Viral load
· The antiviral effect of BI 207127 was dose related
· VL decreases by ≥2 log10 were achieved in the majority of patients receiving doses of 400 mg or 800 mg q8h (Table 2)
· Mean (median) VL drops in the morning of Day 5 (log10 steps; Figure 2) were
- 0.6 (0.4) receiving 100 mg
- 1.1 (0.8) receiving 200 mg
- 1.9 (1.3) receiving 400 mg
- 3.1 (3.8) receiving 800 mg
· No response was seen with placebo
· No breakthrough was observed during treatment
· In the group receiving 800 mg, 5/9 patients showed a ≥4 log10 maximal drop in VL, 2/9 patients achieved VL <25 IU/mL
-- The antiviral effect persisted at least 24 hours after the last drug intake (Figure 3)
Safety profile
Overall AEs were rated mild or moderate and were not considered dose-related (Table 3)
Investigators judged tolerability of BI 207127 as good in 88% (n=32/36) of active-treated patients
Two cases of rash were reported, these two patients exhibited the highest PK exposures
- The only serious adverse event (SAE) related to the intake of BI207127 was a moderate generalized erythema with facial involvement. This patient was receiving 800 mg q8h and the SAE resolved within 2 days after discontinuation of BI207127 and after antihistaminic treatment
- Another patient reported rash (800 mg q8h) which was mild, localized and transient under continued treatment
Laboratory parameters did not show any relevant changes from baseline. There were no signs of liver, kidney or haematotoxicity (Table 4)
Safety and antiviral activity of BI 201335, a new HCV NS3 protease inhibitor
59th Annual Meeting of the American Association
for the Study of Liver Diseases (AASLD)
Oct 31-Nov 1 2008
San Francisco, CA Back
Safety and antiviral activity of BI 201335, a new HCV NS3 protease inhibitor, in treatment-naïve patients with chronic hepatitis C genotype 1 infection given as monotherapy and in combination with peginterferon alfa-2a (P) and ribavirin (R)
Reported by Jules Levin
AASLD Nov 4 2008 San Francisco, CA
Manns, Michael P.1; Bourliere, Marc2; Benhamou, Yves3; Pol, Stanislas4; Bonacini, Maurizio5; Berg, Thomas6; Trepo, Christian7; Wright, David8; Calleja, Jose L.9; Steinmann, Gerhard10; Huang, David B.11; Mikl, Jaromir11; Kukolj, George12; Stern, Jerry O.10, 11
1Medizinische Hochschule Hannover, Zentrum Innere Medizin, Hannover, Germany; 2Hopital Saint Joseph, Marseille, France; 3Hopital Pitie Salpetriere, Paris, France; 4Hopital Cochin, Paris, France; 5California Pacific Medical Center Research Institute, San Francisco, CA, USA; 6Charite Berlin Campus Virchow-Klinikum, Berlin, Germany; 7Hopital Hotel Dieu, Lyon, France; 8Central Texas Clinical Research, Austin, TX, USA; 9Hospital Universitario Puerta de Hierro, Madrid, Spain; 10Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; 11Boehringer Ingelheim Pharmaceuticals Ridgefield, CT, USA; 12Boehringer Ingelheim (Canada) Ltd, Laval, Canada
AUTHOR DISCUSSION AND CONCLUSIONS
BI 201335 induced a pronounced virologic response typically within 2 to 4 days of initiation of monotherapy (from Jules: median maximal -4.2 logs in high dose group of 240 mg given for 14 days monotherapy)
-- 96.2% of patients achieved >2 log10 viral load decline during 14 days of BI 201335 monotherapy
-- 100% of patients in the 48 mg, 120 mg and 240 mg dose groups who received BI201335 achieved >2.8 log10 drop in VL during the first few days of monotherapy
-- The initial virologic response during monotherapy was not maintained; VL breakthrough occurred in the majority of patients by Day 14
BI 201335 given once daily as monotherapy for 14 days, followed by combination therapy with PegIFN/RBV for an additional 14 days, was well tolerated at all dosage levels among treatment-naïve patients
With the exception of an increased incidence of unconjugated hyperbilirubinemia at higher dosage levels, AEs were generally mild to moderate in severity and not considered to be related to study drug, and no patients discontinued monotherapy because of study drug_related AEs
-- AEs observed were commonly associated with PegIFN/RBV treatment
The results of this analysis support further study of BI 201335 once daily as combination therapy for treatment-naïve patients with chronic HCV infection
ABSTRACT
Background: BI201335 is a HCV NS3 protease inhibitor (EC50 of 3-6 nM). A multiple rising dose study evaluated safety and antiviral activity in treatment-naive patients (pts) with chronic HCV genotype-1 infection as monotherapy for 14 days followed by triple combination therapy with P+R for an additional 14 days.
Methods: 34 patients (France, Germany, Spain, USA) with a Metavir fibrosis score of 0-3 and no prior therapy with any IFN or R were randomized (2 placebo:6 active) to 4 dose groups of once-daily (qd) BI201335: 20 mg (n=8), 48 mg (n=9), 120 mg (n=9), or 240 mg (n=8). BI201335 was given as monotherapy for 14 days. Pts with <1 log10 decrease in Day 10 viral load (VL) had BI201335 discontinued after Day 14. Pts with a ≥1 log10 decrease in Day 10 VL continued BI201335 on Day 15 and added P(180ug/week) + R(weight based) for triple combination therapy through Day 28. The primary endpoint was ≥2 log10 VL reduction at any time to Day 14. Plasma HCV-RNA levels were measured with Roche COBAS TaqMan (LLOQ 25 IU/mL).
Results:
33 pts were white, 1 was Asian, 27 were male, mean age = 48.9±11.1 years, mean body weight 79.1±17.5 kg, and median (range) baseline VL was 6.8 (4.7-7.7) log10. There were no significant demographic differences between dose groups. BI201335 was well tolerated. No pts discontinued treatment during monotherapy due to adverse events (AEs). AEs observed were typical for P+R. One serious AE, asthenia, occurred in the 20 mg dose cohort 6 days after initiating P+R. Rapid decline of VL was observed in all pts with maximal decline 2-4 days after starting BI201335. With the exception of 1 pt in the 20 mg cohort, all pts on BI201335 achieved > 2 log10 VL decline during the monotherapy period. Median (range) maximal reductions in VL during 14 day monotherapy for the 20 mg, 48 mg, 120 mg, and 240 mg groups were 3.0 (1.5-3.9), 3.6 (3.1-3.8), 3.7 (3.3-4.1), and 4.2 (3.6-4.8) log10, respectively. No significant change in VL was observed with placebo. VL rebound during treatment was seen in the first 14 days of monotherapy in a majority of patients from all dose groups. Population sequencing of the NS3/4A protease at baseline and rebound during treatment revealed selection of variants that confer in vitro resistance to BI201335.
Conclusion: BI 201335 as monotherapy for 14 days followed by combination with P+R for additional 14 days was well tolerated, and induced a strong and rapid antiviral response. The results support further study of BI201335 as a once-daily potent antiviral for treatment-naïve HCV patients.
INTRODUCTION
BI 201335 is a low molecular weight, peptidomimetic serine protease inhibitor (EC50 of 3-6 nM) that exhibits potent and specific inhibitory activity against the HCV serine protease (NS3/NS4) required for the maturation of HCV viral polyprotein
-- This mechanism of action suggests that BI 201335 in combination with other HCV therapies, has the potential to be an effective drug for the treatment of chronic HCV infection
The safety and pharmacokinetics of BI 201335 have been characterized in an escalating single dose study (trial 1220.3) and in a multiple rising dose, 21- to 28-day trial (1220.6) in healthy volunteers
In Trial 1220.3, treatment with BI 201335 was safe and tolerable in all single dose levels (4 mg to 1200 mg) studied
In Trial 1220.6, 21 to 28 days of treatment with BI 201335 was safe and generally well tolerated across all dose levels studied (20, 48, 120, and 240 mg once daily). No relevant clinical AEs or laboratory abnormalities were reported for the 20 mg and 48 mg groups
-- At higher doses an increased incidence of headache, gastrointestinal symptoms and unconjugated hyperbilirubinemia was observed
-- The 120 mg dose was associated with slight increases of indirect bilirubin in 3/6 subjects
-- The 240 mg dose was also well tolerated, but all 6 subjects experienced reversible indirect hyperbilirubinemia up to 2.5 x ULN
Subjects with Gilbert's polymorphism (GP) (UGT1A1*28) were also studied in Trial 1220.6. Of the 9 subjects with GP, all 5 subjects who were homozygous for Gilbert's polymorphisms experienced reversible indirect bilirubin elevations in the serum up to 4.8 x ULN compared to subjects (n=4) with heterozygous polymorphisms who experienced smaller elevations of indirect bilirubin
These data suggest an association between the UGT1A1 polymorphisms and unconjugated hyperbilirubinemia with high doses of BI 201335
Steady state pharmacokinetic parameters of BI 201335 from trial 1220.6 indicate that BI 201335 NA has a long half life (t1/2, ss = 22.3h-30.9h) which supports once daily dosing
METHODS
Trial 1220.2 is a phase 1b, multinational study that is evaluating the safety, efficacy, and PK data of multiple rising doses of BI 201335 in HCV genotype 1_infected, treatment-naïve (double-blind, placebo-controlled within dose cohorts), and treatment-experienced (open-label, in combination with pegylated interferon alpha-2a and ribavirin [PegIFN/RBV]; Manns MP, et al, AASLD 2008, Abstract 1882) patients
The current interim analyses review the safety and virologic response during 14 days of BI201335 monotherapy followed by an additional 14 days of treatment with BI 201335 in combination with PegIFN/RBV in treatment-naïve patients
Main criteria for eligibility include: no prior therapy with IFN, PegIFN, or RBV for acute or chronic hepatitis C infection; aged ≥18 years; HCV genotype 1 (1a, 1b, or mixed 1a/1b) confirmed by genotype analysis at screening; HCV Ab positive confirmation or detectable VL at least 6 months prior to screening; VL ≥100,000 IU/mL at screening; histologic evidence within 24 months prior to study enrollment of any degree of chronic necroinflammatory activity, or the presence of fibrosis (Ishak grade 1_4 or METAVIR grade 1_3)
Four dose levels were evaluated: 20 mg, 48 mg, 120 mg and 240 mg. For each dosage group, patients received either BI 201335 (n=6 or 7) or placebo (n=2) (Figure 1)
The effective target dose was selected based on PK models derived from preclinical data and from clinical PK data in trial 1220.6, a 4-week multiple rising dose study of BI 201335 in healthy volunteers, to meet a target median steady state trough plasma level (Cmin) of ≥17 ng/mL. This target exposure was reached with a single dose of 20 mg once daily, which was the first dose administered to treatment-naive patients
-- A data monitoring committee reviewed safety, efficacy, and PK data to ensure patients received a safe and virologically relevant dose
Plasma HCV RNA levels were measured using the Roche COBAS TaqMan (lower limit of quantification: 25 IU/mL; lower limit of detection: 10 IU/mL)
Patients with <1 log10 decrease in VL from baseline to Day 10 ended study at Day 14
Patients with ≥1 log10 decrease in VL from baseline to Day 10 received combination therapy of BI 201335 and standard doses of PegIFN alfa-2a/RBV from Days 15 to 28
-- After Day 28, at the discretion of the investigator, patients could continue to receive standard of care (SOC), PegIFN alfa-2a or 2b/RBV, up to Week 48
The primary efficacy endpoint was virologic response (VR), defined as a ≥ 2 log10 reduction in VL from baseline at any time point measured up to Day 14
Secondary efficacy endpoints included change from baseline in VL on Day 14; rapid virologic response (RVR), defined as undetectable VL (<10 IU/mL) on Day 28; end-of-treatment response (ETR), defined as undetectable (<10 IU/mL) VL at Week 48, and SVR
Primary safety endpoints include AEs, serious AEs (SAEs), and changes in laboratory abnormalities and test values over time
Secondary safety endpoints include the occurrence of AEs, by severity and by action taken with regard to test drug, and discontinuations due to AEs
Patients were monitored frequently for VL, treatment-emergent AEs, and laboratory abnormalities
--- VL was monitored on Days 1-4, 6, 10, 14 and 28
- VL was also measured on Day 21 in those patients with >1 log10 reduction in VL by Day 14
- For patients continuing with SOC, additional VL measurements were taken after Day 28 to monitor for early virologic response (EVR), end of PegIFN/RBV treatment response and sustained virologic response (SVR)
RESULTS
Baseline demographics
Thirty-four patients with no prior exposure to PegIFN or RBV were randomized to study drug or placebo within each of the 4 dose groups of once-daily BI 201335 or placebo. There were no significant differences in patient characteristics between study groups at baseline (Table 1)
Efficacy
With the exception of 1 patient in the 20 mg treatment group, all patients receiving BI 201335 (n=25, 96.2%) achieved the primary efficacy endpoint of >2 log10 VL decline during 14 days of monotherapy (Figure 2)
aVL not measured at Day 21 if <1 log10 VL reduction by Day 14 (8/8 patients in placebo group did not achieve <1 log10 VL reduction by Day 14); VL=viral load; PegIFN/RBV, pegylated interferon alpha-2a and ribavirin.
VL decline was rapid; maximal decline was typically reached 2 to 4 days after starting monotherapy (Table 2)
No significant change in VL was observed in patients in the placebo-control groups
Virologic breakthrough (defined as greater than 0.8 log10 increase in VL from baseline) during treatment was seen in the first 14 days of monotherapy in the majority of patients in all dose groups
Amplification of the NS3/NS4A protease segment followed by population-based sequencing of baseline and viral rebound samples demonstrated genotypic changes at specific residues within the NS3 protease domain consistent with resistant mutants that were previously characterized in in vitro resistance studies
Preliminary phenotypic characterization of the mutant NS3 protease domains in the context of the subgenomic replicon demonstrated shifts in the sensitivity to inhibition by BI 201335 consistent with previously characterized point mutants
Safety and tolerability
No dose-dependent increases in AEs were observed (Table 3)
Reported AEs were judged by the investigators to be unrelated to study drug and were typical of treatment with PegIFN/RBV, including fatigue, nausea, rash, headache, gastrointestinal tract disorders, and anemia
-- During the 14 days of BI 201335 monotherapy, diarrhea was reported in 1 placebo-treated patient and in 2 patients in the 48 mg BI 201335 group. There was no indication of any BI 201335 dose-related gastrointestinal effects
-- During the 14 days of BI 201335 monotherapy, no rash was reported in any study patient, however erythema was reported in 1 patient in the 20 mg BI 201335 group
-- Of note, during the triple combination treatment period (Days 15-28) with BI 201335 and PegIFN/RBV, a macular rash was reported in 2 patients: 1 in the 48 mg group and 1 in the 240 mg group. After 30 days following the completion of BI 201335 study treatment, new skin adverse events, including rash and erythema, continued to be reported on PegIFN/RBV follow-on treatment
One serious AE, asthenia, occurred in 1 patient in the BI 201335 20 mg dose cohort 6 days following initiation of therapy with PegIFN/RBV
No patients discontinued treatment during monotherapy because of AEs
No deaths were reported.
Changes in bilirubin were observed with increasing doses of BI 201335 (Table 4) -- At higher doses, an increased incidence of unconjugated hyperbilirubinemia was observed
No other dose-dependent increase in clinical laboratory parameters was observed
REFERENCES
1. Viral hepatitis fact sheet, updated July 21, 2008. Centers for Disease Control and Prevention Web site.
http://www.cdc.gov/hepatitis/HCV/HCVfaq.htm#section1. Accessed September 15, 2008.
2. Dienstag JL, McHutchison JG. American Gastroenterological Association medical position statement on the management of hepatitis C. Gastroenterology. 2006;130:225-230.
for the Study of Liver Diseases (AASLD)
Oct 31-Nov 1 2008
San Francisco, CA Back
Safety and antiviral activity of BI 201335, a new HCV NS3 protease inhibitor, in treatment-naïve patients with chronic hepatitis C genotype 1 infection given as monotherapy and in combination with peginterferon alfa-2a (P) and ribavirin (R)
Reported by Jules Levin
AASLD Nov 4 2008 San Francisco, CA
Manns, Michael P.1; Bourliere, Marc2; Benhamou, Yves3; Pol, Stanislas4; Bonacini, Maurizio5; Berg, Thomas6; Trepo, Christian7; Wright, David8; Calleja, Jose L.9; Steinmann, Gerhard10; Huang, David B.11; Mikl, Jaromir11; Kukolj, George12; Stern, Jerry O.10, 11
1Medizinische Hochschule Hannover, Zentrum Innere Medizin, Hannover, Germany; 2Hopital Saint Joseph, Marseille, France; 3Hopital Pitie Salpetriere, Paris, France; 4Hopital Cochin, Paris, France; 5California Pacific Medical Center Research Institute, San Francisco, CA, USA; 6Charite Berlin Campus Virchow-Klinikum, Berlin, Germany; 7Hopital Hotel Dieu, Lyon, France; 8Central Texas Clinical Research, Austin, TX, USA; 9Hospital Universitario Puerta de Hierro, Madrid, Spain; 10Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; 11Boehringer Ingelheim Pharmaceuticals Ridgefield, CT, USA; 12Boehringer Ingelheim (Canada) Ltd, Laval, Canada
AUTHOR DISCUSSION AND CONCLUSIONS
BI 201335 induced a pronounced virologic response typically within 2 to 4 days of initiation of monotherapy (from Jules: median maximal -4.2 logs in high dose group of 240 mg given for 14 days monotherapy)
-- 96.2% of patients achieved >2 log10 viral load decline during 14 days of BI 201335 monotherapy
-- 100% of patients in the 48 mg, 120 mg and 240 mg dose groups who received BI201335 achieved >2.8 log10 drop in VL during the first few days of monotherapy
-- The initial virologic response during monotherapy was not maintained; VL breakthrough occurred in the majority of patients by Day 14
BI 201335 given once daily as monotherapy for 14 days, followed by combination therapy with PegIFN/RBV for an additional 14 days, was well tolerated at all dosage levels among treatment-naïve patients
With the exception of an increased incidence of unconjugated hyperbilirubinemia at higher dosage levels, AEs were generally mild to moderate in severity and not considered to be related to study drug, and no patients discontinued monotherapy because of study drug_related AEs
-- AEs observed were commonly associated with PegIFN/RBV treatment
The results of this analysis support further study of BI 201335 once daily as combination therapy for treatment-naïve patients with chronic HCV infection
ABSTRACT
Background: BI201335 is a HCV NS3 protease inhibitor (EC50 of 3-6 nM). A multiple rising dose study evaluated safety and antiviral activity in treatment-naive patients (pts) with chronic HCV genotype-1 infection as monotherapy for 14 days followed by triple combination therapy with P+R for an additional 14 days.
Methods: 34 patients (France, Germany, Spain, USA) with a Metavir fibrosis score of 0-3 and no prior therapy with any IFN or R were randomized (2 placebo:6 active) to 4 dose groups of once-daily (qd) BI201335: 20 mg (n=8), 48 mg (n=9), 120 mg (n=9), or 240 mg (n=8). BI201335 was given as monotherapy for 14 days. Pts with <1 log10 decrease in Day 10 viral load (VL) had BI201335 discontinued after Day 14. Pts with a ≥1 log10 decrease in Day 10 VL continued BI201335 on Day 15 and added P(180ug/week) + R(weight based) for triple combination therapy through Day 28. The primary endpoint was ≥2 log10 VL reduction at any time to Day 14. Plasma HCV-RNA levels were measured with Roche COBAS TaqMan (LLOQ 25 IU/mL).
Results:
33 pts were white, 1 was Asian, 27 were male, mean age = 48.9±11.1 years, mean body weight 79.1±17.5 kg, and median (range) baseline VL was 6.8 (4.7-7.7) log10. There were no significant demographic differences between dose groups. BI201335 was well tolerated. No pts discontinued treatment during monotherapy due to adverse events (AEs). AEs observed were typical for P+R. One serious AE, asthenia, occurred in the 20 mg dose cohort 6 days after initiating P+R. Rapid decline of VL was observed in all pts with maximal decline 2-4 days after starting BI201335. With the exception of 1 pt in the 20 mg cohort, all pts on BI201335 achieved > 2 log10 VL decline during the monotherapy period. Median (range) maximal reductions in VL during 14 day monotherapy for the 20 mg, 48 mg, 120 mg, and 240 mg groups were 3.0 (1.5-3.9), 3.6 (3.1-3.8), 3.7 (3.3-4.1), and 4.2 (3.6-4.8) log10, respectively. No significant change in VL was observed with placebo. VL rebound during treatment was seen in the first 14 days of monotherapy in a majority of patients from all dose groups. Population sequencing of the NS3/4A protease at baseline and rebound during treatment revealed selection of variants that confer in vitro resistance to BI201335.
Conclusion: BI 201335 as monotherapy for 14 days followed by combination with P+R for additional 14 days was well tolerated, and induced a strong and rapid antiviral response. The results support further study of BI201335 as a once-daily potent antiviral for treatment-naïve HCV patients.
INTRODUCTION
BI 201335 is a low molecular weight, peptidomimetic serine protease inhibitor (EC50 of 3-6 nM) that exhibits potent and specific inhibitory activity against the HCV serine protease (NS3/NS4) required for the maturation of HCV viral polyprotein
-- This mechanism of action suggests that BI 201335 in combination with other HCV therapies, has the potential to be an effective drug for the treatment of chronic HCV infection
The safety and pharmacokinetics of BI 201335 have been characterized in an escalating single dose study (trial 1220.3) and in a multiple rising dose, 21- to 28-day trial (1220.6) in healthy volunteers
In Trial 1220.3, treatment with BI 201335 was safe and tolerable in all single dose levels (4 mg to 1200 mg) studied
In Trial 1220.6, 21 to 28 days of treatment with BI 201335 was safe and generally well tolerated across all dose levels studied (20, 48, 120, and 240 mg once daily). No relevant clinical AEs or laboratory abnormalities were reported for the 20 mg and 48 mg groups
-- At higher doses an increased incidence of headache, gastrointestinal symptoms and unconjugated hyperbilirubinemia was observed
-- The 120 mg dose was associated with slight increases of indirect bilirubin in 3/6 subjects
-- The 240 mg dose was also well tolerated, but all 6 subjects experienced reversible indirect hyperbilirubinemia up to 2.5 x ULN
Subjects with Gilbert's polymorphism (GP) (UGT1A1*28) were also studied in Trial 1220.6. Of the 9 subjects with GP, all 5 subjects who were homozygous for Gilbert's polymorphisms experienced reversible indirect bilirubin elevations in the serum up to 4.8 x ULN compared to subjects (n=4) with heterozygous polymorphisms who experienced smaller elevations of indirect bilirubin
These data suggest an association between the UGT1A1 polymorphisms and unconjugated hyperbilirubinemia with high doses of BI 201335
Steady state pharmacokinetic parameters of BI 201335 from trial 1220.6 indicate that BI 201335 NA has a long half life (t1/2, ss = 22.3h-30.9h) which supports once daily dosing
METHODS
Trial 1220.2 is a phase 1b, multinational study that is evaluating the safety, efficacy, and PK data of multiple rising doses of BI 201335 in HCV genotype 1_infected, treatment-naïve (double-blind, placebo-controlled within dose cohorts), and treatment-experienced (open-label, in combination with pegylated interferon alpha-2a and ribavirin [PegIFN/RBV]; Manns MP, et al, AASLD 2008, Abstract 1882) patients
The current interim analyses review the safety and virologic response during 14 days of BI201335 monotherapy followed by an additional 14 days of treatment with BI 201335 in combination with PegIFN/RBV in treatment-naïve patients
Main criteria for eligibility include: no prior therapy with IFN, PegIFN, or RBV for acute or chronic hepatitis C infection; aged ≥18 years; HCV genotype 1 (1a, 1b, or mixed 1a/1b) confirmed by genotype analysis at screening; HCV Ab positive confirmation or detectable VL at least 6 months prior to screening; VL ≥100,000 IU/mL at screening; histologic evidence within 24 months prior to study enrollment of any degree of chronic necroinflammatory activity, or the presence of fibrosis (Ishak grade 1_4 or METAVIR grade 1_3)
Four dose levels were evaluated: 20 mg, 48 mg, 120 mg and 240 mg. For each dosage group, patients received either BI 201335 (n=6 or 7) or placebo (n=2) (Figure 1)
The effective target dose was selected based on PK models derived from preclinical data and from clinical PK data in trial 1220.6, a 4-week multiple rising dose study of BI 201335 in healthy volunteers, to meet a target median steady state trough plasma level (Cmin) of ≥17 ng/mL. This target exposure was reached with a single dose of 20 mg once daily, which was the first dose administered to treatment-naive patients
-- A data monitoring committee reviewed safety, efficacy, and PK data to ensure patients received a safe and virologically relevant dose
Plasma HCV RNA levels were measured using the Roche COBAS TaqMan (lower limit of quantification: 25 IU/mL; lower limit of detection: 10 IU/mL)
Patients with <1 log10 decrease in VL from baseline to Day 10 ended study at Day 14
Patients with ≥1 log10 decrease in VL from baseline to Day 10 received combination therapy of BI 201335 and standard doses of PegIFN alfa-2a/RBV from Days 15 to 28
-- After Day 28, at the discretion of the investigator, patients could continue to receive standard of care (SOC), PegIFN alfa-2a or 2b/RBV, up to Week 48
The primary efficacy endpoint was virologic response (VR), defined as a ≥ 2 log10 reduction in VL from baseline at any time point measured up to Day 14
Secondary efficacy endpoints included change from baseline in VL on Day 14; rapid virologic response (RVR), defined as undetectable VL (<10 IU/mL) on Day 28; end-of-treatment response (ETR), defined as undetectable (<10 IU/mL) VL at Week 48, and SVR
Primary safety endpoints include AEs, serious AEs (SAEs), and changes in laboratory abnormalities and test values over time
Secondary safety endpoints include the occurrence of AEs, by severity and by action taken with regard to test drug, and discontinuations due to AEs
Patients were monitored frequently for VL, treatment-emergent AEs, and laboratory abnormalities
--- VL was monitored on Days 1-4, 6, 10, 14 and 28
- VL was also measured on Day 21 in those patients with >1 log10 reduction in VL by Day 14
- For patients continuing with SOC, additional VL measurements were taken after Day 28 to monitor for early virologic response (EVR), end of PegIFN/RBV treatment response and sustained virologic response (SVR)
RESULTS
Baseline demographics
Thirty-four patients with no prior exposure to PegIFN or RBV were randomized to study drug or placebo within each of the 4 dose groups of once-daily BI 201335 or placebo. There were no significant differences in patient characteristics between study groups at baseline (Table 1)
Efficacy
With the exception of 1 patient in the 20 mg treatment group, all patients receiving BI 201335 (n=25, 96.2%) achieved the primary efficacy endpoint of >2 log10 VL decline during 14 days of monotherapy (Figure 2)
aVL not measured at Day 21 if <1 log10 VL reduction by Day 14 (8/8 patients in placebo group did not achieve <1 log10 VL reduction by Day 14); VL=viral load; PegIFN/RBV, pegylated interferon alpha-2a and ribavirin.
VL decline was rapid; maximal decline was typically reached 2 to 4 days after starting monotherapy (Table 2)
No significant change in VL was observed in patients in the placebo-control groups
Virologic breakthrough (defined as greater than 0.8 log10 increase in VL from baseline) during treatment was seen in the first 14 days of monotherapy in the majority of patients in all dose groups
Amplification of the NS3/NS4A protease segment followed by population-based sequencing of baseline and viral rebound samples demonstrated genotypic changes at specific residues within the NS3 protease domain consistent with resistant mutants that were previously characterized in in vitro resistance studies
Preliminary phenotypic characterization of the mutant NS3 protease domains in the context of the subgenomic replicon demonstrated shifts in the sensitivity to inhibition by BI 201335 consistent with previously characterized point mutants
Safety and tolerability
No dose-dependent increases in AEs were observed (Table 3)
Reported AEs were judged by the investigators to be unrelated to study drug and were typical of treatment with PegIFN/RBV, including fatigue, nausea, rash, headache, gastrointestinal tract disorders, and anemia
-- During the 14 days of BI 201335 monotherapy, diarrhea was reported in 1 placebo-treated patient and in 2 patients in the 48 mg BI 201335 group. There was no indication of any BI 201335 dose-related gastrointestinal effects
-- During the 14 days of BI 201335 monotherapy, no rash was reported in any study patient, however erythema was reported in 1 patient in the 20 mg BI 201335 group
-- Of note, during the triple combination treatment period (Days 15-28) with BI 201335 and PegIFN/RBV, a macular rash was reported in 2 patients: 1 in the 48 mg group and 1 in the 240 mg group. After 30 days following the completion of BI 201335 study treatment, new skin adverse events, including rash and erythema, continued to be reported on PegIFN/RBV follow-on treatment
One serious AE, asthenia, occurred in 1 patient in the BI 201335 20 mg dose cohort 6 days following initiation of therapy with PegIFN/RBV
No patients discontinued treatment during monotherapy because of AEs
No deaths were reported.
Changes in bilirubin were observed with increasing doses of BI 201335 (Table 4) -- At higher doses, an increased incidence of unconjugated hyperbilirubinemia was observed
No other dose-dependent increase in clinical laboratory parameters was observed
REFERENCES
1. Viral hepatitis fact sheet, updated July 21, 2008. Centers for Disease Control and Prevention Web site.
http://www.cdc.gov/hepatitis/HCV/HCVfaq.htm#section1. Accessed September 15, 2008.
2. Dienstag JL, McHutchison JG. American Gastroenterological Association medical position statement on the management of hepatitis C. Gastroenterology. 2006;130:225-230.
Monday, April 27, 2009
Ground-Breaking Combination of 2 All-Oral Agents
Ground-Breaking Combination of 2 All-Oral Agents Demonstrates Potential as Hepatitis C Treatment Regimen (ITMN-191 protease + R7128 NRTI)
http://pr-usa.net
Roche, InterMune, Inc. and Pharmasset today announced the first results from their innovative, interferon-free regimen of direct acting antiviral (DAA) combination therapy for the treatment of patients chronically infected with the hepatitis C virus (HCV)(1). The study combined two oral DAAs, R7227 (also known as ITMN-191) and R7128, for the first time in patients. There were no serious adverse events reported during the 14 days of dosing, and the reductions in levels of HCV RNA were significant.
Results of the INFORM-1 study were presented today during the late-breaker session at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL) in Copenhagen.
The trial, conducted in centers in New Zealand and Australia, is the first to investigate the combination of two oral antiviral medicines in the absence of interferon and ribavirin. The results demonstrated for the first time that the combination of an oral protease inhibitor and an oral nucleoside polymerase inhibitor resulted in significant HCV viral load reduction in patients with HCV. Roche is developing R7227, a protease inhibitor, with InterMune, and R7128, a nucleoside polymerase inhibitor, with Pharmasset.
Further studies will test the activity and safety of the combination of R7227 and R7128 with and without interferon and/or ribavirin. The current standard of care for HCV is a combination of pegylated interferon plus ribavirin, which delivers overall sustained virologic response rates (SVR) of 50-60 percent.
"These are exciting times in our fight against hepatitis C, and the investigation of the innovative oral treatment regimen in INFORM-1, if validated in further study, may radically change future treatment strategies in our patients with chronic HCV infection," said Edward Gane, M.D., Associate Professor, University of Auckland and Director, Auckland Clinical Studies Limited. "The initial results from this study of the R7227/R7128 combination raise hopes of the possibility for an interferon-free treatment regimen, as well as the potential for a shorter, more potent interferon-based regimen."
INFORM-1 Results in Brief
INFORM-1 is a randomized, double-blind, ascending dose Phase I trial which has enrolled a total of 57 patients.
Patients receiving the combination of R7227 and R7128 for 14 days -- without pegylated interferon or ribavirin -- experienced a median reduction in viral levels of -4.8 to -5.2 log(10) IU/mL in the highest doses tested. The addition of R7128 to R7227 resulted in sustained viral load reductions over the dosing period, with aproximately 63 percent of patients experiencing a decrease in viral levels below the quantification limit of the diagnostic assay (less than 40 IU/mL). Furthermore, 25 percent of patients in the highest dosage groups were below the limit of detection of the virus in their blood (less than 15 IU/mL) after 14 days.
In the early low-dose groups, after only three days of dosing, the mean reduction in viral load levels was 0.6 log(10) IU/mL greater with combination treatment (-2.9), compared to the performance of the individual compounds when administered as a single agent (-0.46 and -1.84 for R7128 and R7227, respectively). This suggests an additive effect for the combination.
No treatment-related serious adverse events (SAEs), no dose reductions and no discontinuations were reported in the study. Pharmacokinetic analysis confirmed that there were no drug-drug interactions between the compounds.
Next Steps in the Development Program
The companies are now exploring twice-daily dosing of R7227 and higher total daily doses (600 mg twice-daily and 900 mg twice-daily) than those explored in the first patient cohorts of INFORM-1. The companies also plan to explore the innovative DAA combination therapy in "treatment-experienced" patients with HCV, or those who did not achieve SVR with a previous interferon-based treatment.
Other Clinical Studies with R7227 and R7128
In addition to clinical studies of combination DAA regimens such as those studied in INFORM-1, R7227 and R7128 each are proceeding rapidly in development in combination with Roche's PEGASYS(R) (peginterferon alfa-2a) and COPEGUS(R) (ribavirin). A Phase IIb study with R7128 has now begun, while a Phase IIb study with R7227 is slated to begin in the summer.
The Foundation and Future of HCV Treatment
Combination therapy of pegylated interferon and ribavirin is the current standard of care for HCV. PEGASYS is the leading treatment for HCV, and also is the pegylated interferon therapy of choice for most HCV antiviral agents in development -- including those developed through collaborations with Roche, as well as those developed by other companies. The collaborations with InterMune and Pharmasset position Roche as a leader in developing innovative treatments for HCV.
Dial-In and Webcast Details
InterMune and Pharmasset will host a live webcast of a discussion of the INFORM-1 results from the EASL conference today, Saturday, April 25, 2009, at 7:00 p.m. CEST (1:00 p.m. EDT). Participating in the discussion will be Dr. Ed Gane, principal investigator in the INFORM-1 trial. Members of management from Roche, InterMune and Pharmasset will also be available to answer questions. A live webcast and slide presentation will be available through the Investor Relations pages of both InterMune and Pharmasset at www.intermune.com or www.pharmasset.com, respectively. Alternatively, interested parties may access the discussion and ask questions by dialing 888-799-0528 (U.S. and Canada) or 973-200-3372 (international), conference ID # 95452531. A webcast replay will be available approximately three hours after the call and will be archived at www.intermune.com and athttp://www.pharmasset.com/.
The teleconference replay will be available for 10 business days following the call and can be accessed by dialing 800-642-1687 (U.S. and Canada) or 706-645-9291 (international), and entering conference ID # 95452531.
The companies recommend logging on at least 15 minutes prior to the start of the webcast to ensure adequate time for any software downloads that may be required.
About R7227 (ITMN-191)
R7227 is a potent, macrocyclic inhibitor of HCV NS3/4A protease activity, and has produced multi-log(10) reductions in levels of HCV levels in chronic HCV patients, when administered for 14 days as monotherapy and when combined with PEGASYS and COPEGUS. R7227 was safe and well-tolerated in these studies.
About R7128
R7128, a cytidine nucleoside analog inhibitor of HCV RNA polymerase, is being developed for the treatment of chronic HCV infection. R7128 has shown potent in vivo activity against all of the most common HCV genotypes (1, 2 and 3). R7128 was safe and well-tolerated when given with PEGASYS and COPEGUS for up to 28 days.
About PEGASYS
PEGASYS, in combination with COPEGUS (ribavirin), is indicated for the treatment of adults with chronic HCV who have compensated liver disease and have not previously been treated with interferon alpha. Efficacy has been demonstrated in patients with compensated liver disease and histological evidence of cirrhosis (Child-Pugh class A) and patients with HIV disease that are clinically stable (e.g., antiretroviral therapy not required or receiving stable antiretroviral therapy). In addition, PEGASYS in combination with COPEGUS is the first and only FDA-approved regimen for the treatment of chronic HCV in patients coinfected with HCV and HIV. PEGASYS is the only pegylated interferon indicated for the treatment of adult patients with chronic hepatitis B (HBeAg positive and HBeAg negative chronic hepatitis B who have compensated liver disease and evidence of viral replication and liver inflammation).
PEGASYS is dosed at 180mcg as a subcutaneous injection taken once a week. COPEGUS is available as a 200mg tablet, and is administered orally two times a day as a split dose. Roche has backed PEGASYS with the most extensive clinical research program ever undertaken in HCV, with major studies initiated to advance treatment for HCV patients with unmet needs, including patients co-infected with HIV and HCV, African Americans, patients with cirrhosis, and patients who have failed to respond to previous therapy.
Important Safety Information About PEGASYS
PEGASYS, alone or in combination with COPEGUS, is indicated for the treatment of adults with chronic hepatitis C virus infection who have compensated liver disease and have not been previously treated with interferon alpha. Patients in whom efficacy was demonstrated included patients with compensated liver disease and histological evidence of cirrhosis (Child-Pugh class A).
Alpha interferons, including PEGASYS(R) (Peginterferon alfa-2a), may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Therapy should be withdrawn in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping PEGASYS therapy (see CONTRAINDICATIONS, WARNINGS, PRECAUTIONS and ADVERSE REACTIONS in complete product information).
Use with Ribavirin. Ribavirin, including COPEGUS(R), may cause birth defects and/or death of the fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin causes hemolytic anemia. The anemia associated with ribavirin therapy may result in a worsening of cardiac disease. Ribavirin is genotoxic and mutagenic and should be considered a potential carcinogen (see CONTRAINDICATIONS, WARNINGS, PRECAUTIONS and ADVERSE REACTIONS in complete product information).
PEGASYS is contraindicated in patients with hypersensitivity to PEGASYS or any of its components, autoimmune hepatitis, and hepatic decompensation (Child-Pugh score greater than 6; class B and C) in cirrhotic CHC monoinfected patients before or during treatment. PEGASYS is also contraindicated in hepatic decompensation with Child-Pugh score greater than or equal to 6 in cirrhotic CHC patients coinfected with HIV before or during treatment. PEGASYS is also contraindicated in neonates and infants because it contains benzyl alcohol. Benzyl alcohol is associated with an increased incidence of neurological and other complications in neonates and infants, which are sometimes fatal. PEGASYS and COPEGUS therapy is additionally contraindicated in patients with a hypersensitivity to COPEGUS or any of its components, in women who are pregnant, men whose female partners are pregnant, and patients with hemoglobinopathies (eg, thalassemia major, sickle-cell anemia).
COPEGUS THERAPY SHOULD NOT BE STARTED UNLESS A REPORT OF A NEGATIVE PREGNANCY TEST HAS BEEN OBTAINED IMMEDIATELY PRIOR TO INITIATION OF THERAPY. Women of childbearing potential and men must use two forms of effective contraception during treatment and during the 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time. If pregnancy should occur during treatment or during 6 months post-therapy, the patient must be advised of the significant teratogenic risk of COPEGUS therapy to the fetus. Healthcare providers and patients are strongly encouraged to immediately report any pregnancy in a patient or partner of a patient during treatment or during 6 months after treatment cessation to the Ribavirin Pregnancy Registry at 1-800-593-2214.
Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including PEGASYS. During treatment, patients' clinical status and hepatic function should be closely monitored, and PEGASYS treatment should be immediately discontinued if decompensation (Child-Pugh score greater than or equal to 6) is observed. Ischemic and hemorrhagic cerebrovascular events have been observed in patients treated with interferon alfa-based therapies, including PEGASYS. Events occurred in patients with few or no reported risk factors for stroke, including patients less than 45 years of age. Because these are spontaneous reports, estimates of frequency cannot be made and causal relationship between interferon alfa-based therapies and these events is difficult to establish.
The most common adverse events reported for PEGASYS and COPEGUS combination therapy observed in clinical trials were fatigue/asthenia (65 percent), headache (43 percent), pyrexia (41 percent), myalgia (40 percent), irritability/anxiety/nervousness (33 percent), insomnia (30 percent), alopecia (28 percent), neutropenia (27 percent), nausea/vomiting (25 percent), rigors (25 percent), anorexia (24 percent), injection site reaction (23 percent), arthralgia (22 percent), depression (20 percent), pruritus (19 percent) and dermatitis (16 percent).
Serious adverse events in hepatitis C trials included neuropsychiatric disorders (homicidal ideation, suicidal ideation, suicide attempt, suicide, psychotic disorder and hallucinations), serious and severe bacterial infections (sepsis), bone marrow toxicity (cytopenia and rarely, aplastic anemia), cardiovascular disorders (hypertension, supraventricular arrhythmias and myocardial infarction), hypersensitivity (including anaphylaxis), endocrine disorders (including thyroid disorders and diabetes mellitus), autoimmune disorders (including idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, psoriasis, lupus, rheumatoid arthritis and interstitial nephritis), pulmonary disorders (dyspnea, pneumonia, bronchiolitis obliterans, interstitial pneumonitis and sarcoidosis), colitis (ulcerative and hemorrhagic/ischemic colitis), pancreatitis, and ophthalmologic disorders (decrease or loss of vision, retinopathy including macular edema and retinal thrombosis/hemorrhages, optic neuritis and papilledema).
Adverse reactions reported during post-approval use of PEGASYS therapy, with and without ribavirin, include hearing impairment, hearing loss, serious skin reactions, including erythema multiforme major, and infections (bacterial, viral and fungal).
About Roche
Hoffmann-La Roche Inc. (Roche), based in Nutley, N.J., is the U.S. pharmaceuticals headquarters of the Roche Group, one of the world's leading research-oriented healthcare groups with core businesses in pharmaceuticals and diagnostics. For more than 100 years in the U.S., Roche has been committed to developing innovative products and services that address prevention, diagnosis and treatment of diseases, thus enhancing people's health and quality of life. For additional information about the U.S. pharmaceuticals business, visit our website http://www.rocheusa.com/. Product and treatment information for U.S. healthcare professionals is available at www.RocheExchange.com.
About InterMune
InterMune is a biotechnology company focused on the research, development and commercialization of innovative therapies in pulmonology and hepatology. InterMune has a pipeline portfolio addressing idiopathic pulmonary fibrosis (IPF) and hepatitis C virus (HCV) infections. The pulmonology portfolio includes the Phase III program, CAPACITY, which is evaluating pirfenidone as a possible therapeutic candidate for the treatment of patients with IPF and a research program focused on pirfenidone analog ITMN-520. The hepatology portfolio includes the HCV protease inhibitor compound R7227 (ITMN-191), a second-generation HCV protease inhibitor research program, and a research program evaluating a new target in hepatology. For additional information about InterMune and its R&D pipeline, please visit www.intermune.com.
About Pharmasset
Pharmasset is a clinical-stage pharmaceutical company committed to discovering, developing and commercializing novel drugs to treat viral infections. Pharmasset's primary focus is on the development of oral therapeutics for the treatment of hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV). Pharmasset is currently developing three product candidates. R7128, an oral treatment for chronic HCV infection, has completed a 4-week clinical trial in combination with PEGASYS plus COPEGUS through a strategic collaboration with Roche, and is initiating a Phase IIb trial. Racivir, which is being developed for the treatment of HIV in combination with other approved HIV drugs, has completed a Phase II clinical trial. PSI-7851, an unpartnered second generation HCV nucleotide analogue recently entered Phase I studies. Additional information is available on the Internet at http://www.pharmasset.com/
Forward-Looking Statements
This news release contains forward-looking statements within the meaning of section 21E of the Securities Exchange Act of 1934, as amended, that reflect the companies' judgments and involve risks and uncertainties as of the date of this release, including without limitation the statements related to anticipated product development timelines. All forward-looking statements and other information included in this press release are based on information available to the companies as of the date hereof, and the companies assume no obligation to update any such forward-looking statements or information. Actual results could differ materially from those described in the forward-looking statements.
Factors that could cause or contribute to such differences include, but are not limited to, those discussed in detail under the heading "Risk Factors" in the companies' most recent annual reports on Form 10-K filed with the SEC and in other periodic reports filed with the SEC. The risks and other factors discussed above should be considered only in connection with the fully discussed risks and other factors discussed in detail in the respective Forms 10-K and in the companies' other periodic reports filed with the SEC, all of which are available via their respective web sites at www.intermune.com and .
All trademarks used or mentioned in this release are protected by law.
- About INFORM-1: www.clinicaltrials.gov
(1) "First-In-Man Demonstration Of Potent Antiviral Activity with a Nucleoside Polymerase (R7128) and Protease (R7227/ITMN-191) Inhibitor Combination in HCV: Safety, Pharmacokinetics, and Virologic Results from INFORM-1," Abstract #1046: to be presented at 44th Annual Meeting of the European Association for the Study of the Liver (EASL) in Copenhagen, Denmark, April 22 - 26, 2009.
Contacts:
Linda Dyson
Roche
973-562-2231 (office)
973-986-5973 (mobile)
Linda.Dyson@roche.com
Jim Goff
Sr. Director, Corp. Comm. & IR
InterMune, Inc.
415-466-2228
jgoff@intermune.com
Richard E. T. Smith, Ph.D.
VP, Investor Relations and Corporate Communications
Pharmasset
609-613-4181
richard.smith@pharmasset.com
Source: Roche; InterMune; Pharmasset
http://pr-usa.net
Roche, InterMune, Inc. and Pharmasset today announced the first results from their innovative, interferon-free regimen of direct acting antiviral (DAA) combination therapy for the treatment of patients chronically infected with the hepatitis C virus (HCV)(1). The study combined two oral DAAs, R7227 (also known as ITMN-191) and R7128, for the first time in patients. There were no serious adverse events reported during the 14 days of dosing, and the reductions in levels of HCV RNA were significant.
Results of the INFORM-1 study were presented today during the late-breaker session at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL) in Copenhagen.
The trial, conducted in centers in New Zealand and Australia, is the first to investigate the combination of two oral antiviral medicines in the absence of interferon and ribavirin. The results demonstrated for the first time that the combination of an oral protease inhibitor and an oral nucleoside polymerase inhibitor resulted in significant HCV viral load reduction in patients with HCV. Roche is developing R7227, a protease inhibitor, with InterMune, and R7128, a nucleoside polymerase inhibitor, with Pharmasset.
Further studies will test the activity and safety of the combination of R7227 and R7128 with and without interferon and/or ribavirin. The current standard of care for HCV is a combination of pegylated interferon plus ribavirin, which delivers overall sustained virologic response rates (SVR) of 50-60 percent.
"These are exciting times in our fight against hepatitis C, and the investigation of the innovative oral treatment regimen in INFORM-1, if validated in further study, may radically change future treatment strategies in our patients with chronic HCV infection," said Edward Gane, M.D., Associate Professor, University of Auckland and Director, Auckland Clinical Studies Limited. "The initial results from this study of the R7227/R7128 combination raise hopes of the possibility for an interferon-free treatment regimen, as well as the potential for a shorter, more potent interferon-based regimen."
INFORM-1 Results in Brief
INFORM-1 is a randomized, double-blind, ascending dose Phase I trial which has enrolled a total of 57 patients.
Patients receiving the combination of R7227 and R7128 for 14 days -- without pegylated interferon or ribavirin -- experienced a median reduction in viral levels of -4.8 to -5.2 log(10) IU/mL in the highest doses tested. The addition of R7128 to R7227 resulted in sustained viral load reductions over the dosing period, with aproximately 63 percent of patients experiencing a decrease in viral levels below the quantification limit of the diagnostic assay (less than 40 IU/mL). Furthermore, 25 percent of patients in the highest dosage groups were below the limit of detection of the virus in their blood (less than 15 IU/mL) after 14 days.
In the early low-dose groups, after only three days of dosing, the mean reduction in viral load levels was 0.6 log(10) IU/mL greater with combination treatment (-2.9), compared to the performance of the individual compounds when administered as a single agent (-0.46 and -1.84 for R7128 and R7227, respectively). This suggests an additive effect for the combination.
No treatment-related serious adverse events (SAEs), no dose reductions and no discontinuations were reported in the study. Pharmacokinetic analysis confirmed that there were no drug-drug interactions between the compounds.
Next Steps in the Development Program
The companies are now exploring twice-daily dosing of R7227 and higher total daily doses (600 mg twice-daily and 900 mg twice-daily) than those explored in the first patient cohorts of INFORM-1. The companies also plan to explore the innovative DAA combination therapy in "treatment-experienced" patients with HCV, or those who did not achieve SVR with a previous interferon-based treatment.
Other Clinical Studies with R7227 and R7128
In addition to clinical studies of combination DAA regimens such as those studied in INFORM-1, R7227 and R7128 each are proceeding rapidly in development in combination with Roche's PEGASYS(R) (peginterferon alfa-2a) and COPEGUS(R) (ribavirin). A Phase IIb study with R7128 has now begun, while a Phase IIb study with R7227 is slated to begin in the summer.
The Foundation and Future of HCV Treatment
Combination therapy of pegylated interferon and ribavirin is the current standard of care for HCV. PEGASYS is the leading treatment for HCV, and also is the pegylated interferon therapy of choice for most HCV antiviral agents in development -- including those developed through collaborations with Roche, as well as those developed by other companies. The collaborations with InterMune and Pharmasset position Roche as a leader in developing innovative treatments for HCV.
Dial-In and Webcast Details
InterMune and Pharmasset will host a live webcast of a discussion of the INFORM-1 results from the EASL conference today, Saturday, April 25, 2009, at 7:00 p.m. CEST (1:00 p.m. EDT). Participating in the discussion will be Dr. Ed Gane, principal investigator in the INFORM-1 trial. Members of management from Roche, InterMune and Pharmasset will also be available to answer questions. A live webcast and slide presentation will be available through the Investor Relations pages of both InterMune and Pharmasset at www.intermune.com or www.pharmasset.com, respectively. Alternatively, interested parties may access the discussion and ask questions by dialing 888-799-0528 (U.S. and Canada) or 973-200-3372 (international), conference ID # 95452531. A webcast replay will be available approximately three hours after the call and will be archived at www.intermune.com and athttp://www.pharmasset.com/.
The teleconference replay will be available for 10 business days following the call and can be accessed by dialing 800-642-1687 (U.S. and Canada) or 706-645-9291 (international), and entering conference ID # 95452531.
The companies recommend logging on at least 15 minutes prior to the start of the webcast to ensure adequate time for any software downloads that may be required.
About R7227 (ITMN-191)
R7227 is a potent, macrocyclic inhibitor of HCV NS3/4A protease activity, and has produced multi-log(10) reductions in levels of HCV levels in chronic HCV patients, when administered for 14 days as monotherapy and when combined with PEGASYS and COPEGUS. R7227 was safe and well-tolerated in these studies.
About R7128
R7128, a cytidine nucleoside analog inhibitor of HCV RNA polymerase, is being developed for the treatment of chronic HCV infection. R7128 has shown potent in vivo activity against all of the most common HCV genotypes (1, 2 and 3). R7128 was safe and well-tolerated when given with PEGASYS and COPEGUS for up to 28 days.
About PEGASYS
PEGASYS, in combination with COPEGUS (ribavirin), is indicated for the treatment of adults with chronic HCV who have compensated liver disease and have not previously been treated with interferon alpha. Efficacy has been demonstrated in patients with compensated liver disease and histological evidence of cirrhosis (Child-Pugh class A) and patients with HIV disease that are clinically stable (e.g., antiretroviral therapy not required or receiving stable antiretroviral therapy). In addition, PEGASYS in combination with COPEGUS is the first and only FDA-approved regimen for the treatment of chronic HCV in patients coinfected with HCV and HIV. PEGASYS is the only pegylated interferon indicated for the treatment of adult patients with chronic hepatitis B (HBeAg positive and HBeAg negative chronic hepatitis B who have compensated liver disease and evidence of viral replication and liver inflammation).
PEGASYS is dosed at 180mcg as a subcutaneous injection taken once a week. COPEGUS is available as a 200mg tablet, and is administered orally two times a day as a split dose. Roche has backed PEGASYS with the most extensive clinical research program ever undertaken in HCV, with major studies initiated to advance treatment for HCV patients with unmet needs, including patients co-infected with HIV and HCV, African Americans, patients with cirrhosis, and patients who have failed to respond to previous therapy.
Important Safety Information About PEGASYS
PEGASYS, alone or in combination with COPEGUS, is indicated for the treatment of adults with chronic hepatitis C virus infection who have compensated liver disease and have not been previously treated with interferon alpha. Patients in whom efficacy was demonstrated included patients with compensated liver disease and histological evidence of cirrhosis (Child-Pugh class A).
Alpha interferons, including PEGASYS(R) (Peginterferon alfa-2a), may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Therapy should be withdrawn in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping PEGASYS therapy (see CONTRAINDICATIONS, WARNINGS, PRECAUTIONS and ADVERSE REACTIONS in complete product information).
Use with Ribavirin. Ribavirin, including COPEGUS(R), may cause birth defects and/or death of the fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin causes hemolytic anemia. The anemia associated with ribavirin therapy may result in a worsening of cardiac disease. Ribavirin is genotoxic and mutagenic and should be considered a potential carcinogen (see CONTRAINDICATIONS, WARNINGS, PRECAUTIONS and ADVERSE REACTIONS in complete product information).
PEGASYS is contraindicated in patients with hypersensitivity to PEGASYS or any of its components, autoimmune hepatitis, and hepatic decompensation (Child-Pugh score greater than 6; class B and C) in cirrhotic CHC monoinfected patients before or during treatment. PEGASYS is also contraindicated in hepatic decompensation with Child-Pugh score greater than or equal to 6 in cirrhotic CHC patients coinfected with HIV before or during treatment. PEGASYS is also contraindicated in neonates and infants because it contains benzyl alcohol. Benzyl alcohol is associated with an increased incidence of neurological and other complications in neonates and infants, which are sometimes fatal. PEGASYS and COPEGUS therapy is additionally contraindicated in patients with a hypersensitivity to COPEGUS or any of its components, in women who are pregnant, men whose female partners are pregnant, and patients with hemoglobinopathies (eg, thalassemia major, sickle-cell anemia).
COPEGUS THERAPY SHOULD NOT BE STARTED UNLESS A REPORT OF A NEGATIVE PREGNANCY TEST HAS BEEN OBTAINED IMMEDIATELY PRIOR TO INITIATION OF THERAPY. Women of childbearing potential and men must use two forms of effective contraception during treatment and during the 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time. If pregnancy should occur during treatment or during 6 months post-therapy, the patient must be advised of the significant teratogenic risk of COPEGUS therapy to the fetus. Healthcare providers and patients are strongly encouraged to immediately report any pregnancy in a patient or partner of a patient during treatment or during 6 months after treatment cessation to the Ribavirin Pregnancy Registry at 1-800-593-2214.
Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including PEGASYS. During treatment, patients' clinical status and hepatic function should be closely monitored, and PEGASYS treatment should be immediately discontinued if decompensation (Child-Pugh score greater than or equal to 6) is observed. Ischemic and hemorrhagic cerebrovascular events have been observed in patients treated with interferon alfa-based therapies, including PEGASYS. Events occurred in patients with few or no reported risk factors for stroke, including patients less than 45 years of age. Because these are spontaneous reports, estimates of frequency cannot be made and causal relationship between interferon alfa-based therapies and these events is difficult to establish.
The most common adverse events reported for PEGASYS and COPEGUS combination therapy observed in clinical trials were fatigue/asthenia (65 percent), headache (43 percent), pyrexia (41 percent), myalgia (40 percent), irritability/anxiety/nervousness (33 percent), insomnia (30 percent), alopecia (28 percent), neutropenia (27 percent), nausea/vomiting (25 percent), rigors (25 percent), anorexia (24 percent), injection site reaction (23 percent), arthralgia (22 percent), depression (20 percent), pruritus (19 percent) and dermatitis (16 percent).
Serious adverse events in hepatitis C trials included neuropsychiatric disorders (homicidal ideation, suicidal ideation, suicide attempt, suicide, psychotic disorder and hallucinations), serious and severe bacterial infections (sepsis), bone marrow toxicity (cytopenia and rarely, aplastic anemia), cardiovascular disorders (hypertension, supraventricular arrhythmias and myocardial infarction), hypersensitivity (including anaphylaxis), endocrine disorders (including thyroid disorders and diabetes mellitus), autoimmune disorders (including idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, psoriasis, lupus, rheumatoid arthritis and interstitial nephritis), pulmonary disorders (dyspnea, pneumonia, bronchiolitis obliterans, interstitial pneumonitis and sarcoidosis), colitis (ulcerative and hemorrhagic/ischemic colitis), pancreatitis, and ophthalmologic disorders (decrease or loss of vision, retinopathy including macular edema and retinal thrombosis/hemorrhages, optic neuritis and papilledema).
Adverse reactions reported during post-approval use of PEGASYS therapy, with and without ribavirin, include hearing impairment, hearing loss, serious skin reactions, including erythema multiforme major, and infections (bacterial, viral and fungal).
About Roche
Hoffmann-La Roche Inc. (Roche), based in Nutley, N.J., is the U.S. pharmaceuticals headquarters of the Roche Group, one of the world's leading research-oriented healthcare groups with core businesses in pharmaceuticals and diagnostics. For more than 100 years in the U.S., Roche has been committed to developing innovative products and services that address prevention, diagnosis and treatment of diseases, thus enhancing people's health and quality of life. For additional information about the U.S. pharmaceuticals business, visit our website http://www.rocheusa.com/. Product and treatment information for U.S. healthcare professionals is available at www.RocheExchange.com.
About InterMune
InterMune is a biotechnology company focused on the research, development and commercialization of innovative therapies in pulmonology and hepatology. InterMune has a pipeline portfolio addressing idiopathic pulmonary fibrosis (IPF) and hepatitis C virus (HCV) infections. The pulmonology portfolio includes the Phase III program, CAPACITY, which is evaluating pirfenidone as a possible therapeutic candidate for the treatment of patients with IPF and a research program focused on pirfenidone analog ITMN-520. The hepatology portfolio includes the HCV protease inhibitor compound R7227 (ITMN-191), a second-generation HCV protease inhibitor research program, and a research program evaluating a new target in hepatology. For additional information about InterMune and its R&D pipeline, please visit www.intermune.com.
About Pharmasset
Pharmasset is a clinical-stage pharmaceutical company committed to discovering, developing and commercializing novel drugs to treat viral infections. Pharmasset's primary focus is on the development of oral therapeutics for the treatment of hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV). Pharmasset is currently developing three product candidates. R7128, an oral treatment for chronic HCV infection, has completed a 4-week clinical trial in combination with PEGASYS plus COPEGUS through a strategic collaboration with Roche, and is initiating a Phase IIb trial. Racivir, which is being developed for the treatment of HIV in combination with other approved HIV drugs, has completed a Phase II clinical trial. PSI-7851, an unpartnered second generation HCV nucleotide analogue recently entered Phase I studies. Additional information is available on the Internet at http://www.pharmasset.com/
Forward-Looking Statements
This news release contains forward-looking statements within the meaning of section 21E of the Securities Exchange Act of 1934, as amended, that reflect the companies' judgments and involve risks and uncertainties as of the date of this release, including without limitation the statements related to anticipated product development timelines. All forward-looking statements and other information included in this press release are based on information available to the companies as of the date hereof, and the companies assume no obligation to update any such forward-looking statements or information. Actual results could differ materially from those described in the forward-looking statements.
Factors that could cause or contribute to such differences include, but are not limited to, those discussed in detail under the heading "Risk Factors" in the companies' most recent annual reports on Form 10-K filed with the SEC and in other periodic reports filed with the SEC. The risks and other factors discussed above should be considered only in connection with the fully discussed risks and other factors discussed in detail in the respective Forms 10-K and in the companies' other periodic reports filed with the SEC, all of which are available via their respective web sites at www.intermune.com and .
All trademarks used or mentioned in this release are protected by law.
- About INFORM-1: www.clinicaltrials.gov
(1) "First-In-Man Demonstration Of Potent Antiviral Activity with a Nucleoside Polymerase (R7128) and Protease (R7227/ITMN-191) Inhibitor Combination in HCV: Safety, Pharmacokinetics, and Virologic Results from INFORM-1," Abstract #1046: to be presented at 44th Annual Meeting of the European Association for the Study of the Liver (EASL) in Copenhagen, Denmark, April 22 - 26, 2009.
Contacts:
Linda Dyson
Roche
973-562-2231 (office)
973-986-5973 (mobile)
Linda.Dyson@roche.com
Jim Goff
Sr. Director, Corp. Comm. & IR
InterMune, Inc.
415-466-2228
jgoff@intermune.com
Richard E. T. Smith, Ph.D.
VP, Investor Relations and Corporate Communications
Pharmasset
609-613-4181
richard.smith@pharmasset.com
Source: Roche; InterMune; Pharmasset
phase IIb clinical trial of R7128 nucleoside polymerase inhibitor for chronic hepatitis C
Roche and Pharmasset start phase IIb clinical trial of R7128 nucleoside polymerase inhibitor for chronic hepatitis C
Sunday, 26-Apr-2009
Pharmasset, Inc. and Roche have announced that the first patient has been dosed in a Phase IIb study of R7128, the nucleoside polymerase inhibitor most advanced in development for the treatment of chronic hepatitis C (HCV).
The trial will evaluate the dose and duration of treatment of R7128 in combination with Roche's PEGASYS(R) (peginterferon alfa-2a) and COPEGUS(R) (ribavirin) - in HCV patients who have not been treated previously. The goal of adding R7128 to the existing standard therapy is to improve rates of sustained virological response (SVR) and to shorten the length of treatment for patients.
R7128 is being developed by Roche and Pharmasset under a partnership agreement entered into in 2004. The first patient dosed in this study triggered a $10 million payment to Pharmasset from Roche.
A Phase I/IIa trial demonstrated the ability of R7128 to generate high rapid virologic response rates (RVR) in combination with PEGASYS and COPEGUS. Unlike protease inhibitors in development, R7128 is active against multiple HCV genotypes and presents a high barrier to the development of resistance.
"We look for the Phase IIb study to further support the efficacy and safety of R7128, and nucleoside polymerase inhibitors as a class," said Michelle Berrey, MD, MPH, Pharmasset's Chief Medical Officer. "We believe nucleoside inhibitors have a number of advantages over other classes of HCV drugs, including a higher barrier to resistance and activity across multiple genotypes, as well as a high level of potency."
"The collaboration with Pharmasset underscores Roche's commitment to develop new therapies that will meet the needs of a growing population of patients with hepatitis C," said Rob Mitchell, Global Head of Roche's Virology business. "We are hopeful that a combination of R7128 and the current gold standard of PEGASYS and COPEGUS can provide a more potent - and potentially shorter - treatment regimen."
These collaborations position Roche as a leader, and they underscore Roche's role as a pioneer, in the next evolution of hepatology treatments.
The Phase IIb trial is anticipated to enroll about 400 HCV-infected patients with genotypes 1 or 4 who have not been treated previously. The primary efficacy endpoint of the trial will be the proportion of patients who achieve an SVR, defined as undetectable levels of HCV (measured by Roche TaqMan assay) 24 weeks after completion of treatment. The trial will be conducted in North America, Europe and Australia. Patients will be enrolled into one of 5 arms:
•24 weeks of total treatment, with R7128 500mg bid in combination with PEGASYS and COPEGUS for 12 weeks, followed by 12 weeks of PEGASYS and COPEGUS ("12+12")
•24 weeks of total treatment, with R7128 1000mg bid in combination with PEGASYS and COPEGUS for 12 weeks, followed by 12 weeks of PEGASYS and COPEGUS ("12+12")
•24 weeks of total treatment, with R7128 1000mg bid in combination with PEGASYS and COPEGUS for 8 weeks, followed by a further 16 weeks of PEGASYS and COPEGUS ("8+16")
•48 weeks of total treatment, with R7128 1000mg bid in combination with PEGASYS and COPEGUS for 12 weeks, followed by a further 36 weeks of PEGASYS and COPEGUS ("12+36")
•A control arm with PEGASYS and COPEGUS for 48 weeks.
Patients in the 24-week arms will discontinue all treatment at week 24 if they have achieved RVR, defined as undetectable levels of HCV at week 4 (a strategy known as "RVR-guided" treatment), and maintain undetectable levels of HCV until week 22. Patients who do not achieve an RVR at week 4 will continue on the standard of care until week 48.
According to the study design, 100 patients will be initially enrolled, equally across all five arms. The remaining 300 will be enrolled following a review of the 12-week data by the data safety monitoring board.
R7128, a cytidine nucleoside analog inhibitor, is being developed for the treatment of chronic HCV infection. R7128 has shown in vitro activity against all of the most common HCV genotypes.
In a 4-week Phase I combination study conducted in 81 treatment-naive patients with chronic HCV, R7128 demonstrated significant short-term antiviral activity with safety and tolerability comparable to placebo with standard of care. Up to 88 percent of patients achieved undetectable levels of HCV (<15 IU/ml) after only 4 weeks of treatment with R7128 1000mg bid and the standard of care, compared to 18.75 percent treated with the standard of care alone. -- In the harder to treat populations of genotype 2 or 3 patients who had not responded to previous therapy, results with R7127 1500mg twice-daily in combination with the standard of care showed that 90 percent of patients achieved undetectable levels of HCV(<15 IU/ml) after 4 weeks, compared to 60 percent in the standard of care arm.
In November 2008, Roche, Pharmasset and InterMune initiated the INFORM-1 trial to investigate the combination of R7128 with InterMune's R7227, a protease inhibitor, in HCV patients. This is the first-ever clinical study to investigate the combination of two oral antiviral medicines in the absence of weekly injections of interferon, or ribavirin. Interim results of this trial will be presented this weekend at the European Association of Liver Disease (EASL) meeting being held in Copenhagen, Denmark.
http://www.pharmasset.com/
Sunday, 26-Apr-2009
Pharmasset, Inc. and Roche have announced that the first patient has been dosed in a Phase IIb study of R7128, the nucleoside polymerase inhibitor most advanced in development for the treatment of chronic hepatitis C (HCV).
The trial will evaluate the dose and duration of treatment of R7128 in combination with Roche's PEGASYS(R) (peginterferon alfa-2a) and COPEGUS(R) (ribavirin) - in HCV patients who have not been treated previously. The goal of adding R7128 to the existing standard therapy is to improve rates of sustained virological response (SVR) and to shorten the length of treatment for patients.
R7128 is being developed by Roche and Pharmasset under a partnership agreement entered into in 2004. The first patient dosed in this study triggered a $10 million payment to Pharmasset from Roche.
A Phase I/IIa trial demonstrated the ability of R7128 to generate high rapid virologic response rates (RVR) in combination with PEGASYS and COPEGUS. Unlike protease inhibitors in development, R7128 is active against multiple HCV genotypes and presents a high barrier to the development of resistance.
"We look for the Phase IIb study to further support the efficacy and safety of R7128, and nucleoside polymerase inhibitors as a class," said Michelle Berrey, MD, MPH, Pharmasset's Chief Medical Officer. "We believe nucleoside inhibitors have a number of advantages over other classes of HCV drugs, including a higher barrier to resistance and activity across multiple genotypes, as well as a high level of potency."
"The collaboration with Pharmasset underscores Roche's commitment to develop new therapies that will meet the needs of a growing population of patients with hepatitis C," said Rob Mitchell, Global Head of Roche's Virology business. "We are hopeful that a combination of R7128 and the current gold standard of PEGASYS and COPEGUS can provide a more potent - and potentially shorter - treatment regimen."
These collaborations position Roche as a leader, and they underscore Roche's role as a pioneer, in the next evolution of hepatology treatments.
The Phase IIb trial is anticipated to enroll about 400 HCV-infected patients with genotypes 1 or 4 who have not been treated previously. The primary efficacy endpoint of the trial will be the proportion of patients who achieve an SVR, defined as undetectable levels of HCV (measured by Roche TaqMan assay) 24 weeks after completion of treatment. The trial will be conducted in North America, Europe and Australia. Patients will be enrolled into one of 5 arms:
•24 weeks of total treatment, with R7128 500mg bid in combination with PEGASYS and COPEGUS for 12 weeks, followed by 12 weeks of PEGASYS and COPEGUS ("12+12")
•24 weeks of total treatment, with R7128 1000mg bid in combination with PEGASYS and COPEGUS for 12 weeks, followed by 12 weeks of PEGASYS and COPEGUS ("12+12")
•24 weeks of total treatment, with R7128 1000mg bid in combination with PEGASYS and COPEGUS for 8 weeks, followed by a further 16 weeks of PEGASYS and COPEGUS ("8+16")
•48 weeks of total treatment, with R7128 1000mg bid in combination with PEGASYS and COPEGUS for 12 weeks, followed by a further 36 weeks of PEGASYS and COPEGUS ("12+36")
•A control arm with PEGASYS and COPEGUS for 48 weeks.
Patients in the 24-week arms will discontinue all treatment at week 24 if they have achieved RVR, defined as undetectable levels of HCV at week 4 (a strategy known as "RVR-guided" treatment), and maintain undetectable levels of HCV until week 22. Patients who do not achieve an RVR at week 4 will continue on the standard of care until week 48.
According to the study design, 100 patients will be initially enrolled, equally across all five arms. The remaining 300 will be enrolled following a review of the 12-week data by the data safety monitoring board.
R7128, a cytidine nucleoside analog inhibitor, is being developed for the treatment of chronic HCV infection. R7128 has shown in vitro activity against all of the most common HCV genotypes.
In a 4-week Phase I combination study conducted in 81 treatment-naive patients with chronic HCV, R7128 demonstrated significant short-term antiviral activity with safety and tolerability comparable to placebo with standard of care. Up to 88 percent of patients achieved undetectable levels of HCV (<15 IU/ml) after only 4 weeks of treatment with R7128 1000mg bid and the standard of care, compared to 18.75 percent treated with the standard of care alone. -- In the harder to treat populations of genotype 2 or 3 patients who had not responded to previous therapy, results with R7127 1500mg twice-daily in combination with the standard of care showed that 90 percent of patients achieved undetectable levels of HCV(<15 IU/ml) after 4 weeks, compared to 60 percent in the standard of care arm.
In November 2008, Roche, Pharmasset and InterMune initiated the INFORM-1 trial to investigate the combination of R7128 with InterMune's R7227, a protease inhibitor, in HCV patients. This is the first-ever clinical study to investigate the combination of two oral antiviral medicines in the absence of weekly injections of interferon, or ribavirin. Interim results of this trial will be presented this weekend at the European Association of Liver Disease (EASL) meeting being held in Copenhagen, Denmark.
http://www.pharmasset.com/
New Phase IIa Data On TMC435 In Patients With Hepatitis C
New Phase IIa Data On TMC435 In Patients With Hepatitis C Presented At The Ongoing EASL - Meeting
www.medicalnewstoday.com
Data were presented from the phase IIa trial (OPERA-1) for TMC435 at the ongoing 44th Annual Meeting of the European Association for the Study of the Liver (EASL) in Copenhagen, Denmark, April 22-26.
TMC435 is an investigational protease inhibitor, being developed by Tibotec in collaboration with Medivir (STO:MVIRB), for the treatment of hepatitis C virus (HCV).
Data for TMC435 in treatment naïve genotype-1 HCV patients have been presented in an oral lecture. Furthermore, data in patients with genotype-1 HCV infection who failed previous IFN-based therapy were presented during a late breaker poster session.
TMC435 in treatment-naïve genotype-1 HCV patients The results from 25, 75 and 200 mg in treatment-naive patients are summarized below:
1. Viral load reduction, (RNA log10 IU/mL), at week 4 on triple therapy groups (SoC and TMC435) was 5.5 and 5.4 log10 IU/mL for the 75 mg and 200 mg TMC435, QD respectively.
2. Undetectable levels (< 10 IU/mL) in 8/9 patients in the 75 mg group and 7/10 in the 200 mg group was observed after 4 weeks of treatment with triple therapy.
3. After 12 weeks (4 weeks triple + 8 weeks SoC), 6/9, 9/9 and 10/10 had undetectable virus (< 10 IU/mL) in the 25mg, 75 and 200 mg groups, respectively.
4. No breakthroughs observed after 4 weeks of triple therapy in any of the groups (25, 75 or 200 mg).
5. No treatment related discontinuations, most AEs were mild to moderate.
6. No evidence of TMC related hepatic, renal, CV or blood (haematopoietic) adverse events.
7. Mild and reversible increases in bilirubin observed in highest dose groups (200 mg).
8. Substantial decreases of liver transaminases were observed.
TMC435 in patients that failed previous IFN-based treatment The results from 75, 150 and 200mg are summarized below:
1. Potent, dose-dependent, antiviral activity after 4 weeks treatment with triple therapy with 4.3, 5.5 and 5.3 log 10 IU/mL reduction for 75, 150 and 200 mg QD groups, respectively, compared to 1.5 in the placebo group
2. Three viral breakthroughs were observed in prior non-responders with G1b, 2 in 75 mg and 1 in the 150 mg QD group.
3. At Day 28, 4/9 (44%), 7/9 (78%) and 7/10 (70%) patients achieved plasma HCV RNA levels <25 IU/mL in the 75, 150 and 200 mg QD treatment groups, respectively, compared with no patients (0/9) in the placebo group
4. 2/9 (22%), 5/9 (56%) and 3/10 (30%) patients in 75, 150 and the 200 mg groups reached undetectable levels (< 10 IU/mL) after 4 weeks of treatment, compared to 0/9 patients on placebo.
5. There were no serious adverse events and no treatment discontinuations due to adverse events, which generally were of mild to moderate grade.
6. Liver enzymes were reduced by TMC treatment.
7. Bilirubin increases were observed in some patients on TMC, mostly with the 200 mg group. These elevations were reversible and generally mild.
Conclusions:
In treatment-naïve patients infected with HCV genotype-1, TMC435 in combination with SoC over 4 weeks of treatment:
- demonstrated potent antiviral activity
- was generally safe and well tolerated
- was not associated with AE-related treatment discontinuations
These results support the development of TMC435 for treatment-naïve patients infected with HCV genotype-1.
In treatment experienced patients infected with HCV genotype 1, 28 days of once-daily treatment with TMC435 (75, 150 and 200 mg) as part of a triple therapy regimen with PEGIFN-2a and RBV:
- demonstrated potent, dose-dependent antiviral activity.
- was generally safe and well tolerated.
- was not associated with AE-related treatment discontinuations.
About hepatitis C
According to the World Health Organization, about 170 million people around the world are infected with chronic HCV and 3 to 4 million people are newly infected each year Chronic infection with HCV can lead to cirrhosis and liver cancer, and is the most common cause of liver transplant in Europe.
For more information on Medivir, please see the company website:http://www.medivir.se
www.medicalnewstoday.com
Data were presented from the phase IIa trial (OPERA-1) for TMC435 at the ongoing 44th Annual Meeting of the European Association for the Study of the Liver (EASL) in Copenhagen, Denmark, April 22-26.
TMC435 is an investigational protease inhibitor, being developed by Tibotec in collaboration with Medivir (STO:MVIRB), for the treatment of hepatitis C virus (HCV).
Data for TMC435 in treatment naïve genotype-1 HCV patients have been presented in an oral lecture. Furthermore, data in patients with genotype-1 HCV infection who failed previous IFN-based therapy were presented during a late breaker poster session.
TMC435 in treatment-naïve genotype-1 HCV patients The results from 25, 75 and 200 mg in treatment-naive patients are summarized below:
1. Viral load reduction, (RNA log10 IU/mL), at week 4 on triple therapy groups (SoC and TMC435) was 5.5 and 5.4 log10 IU/mL for the 75 mg and 200 mg TMC435, QD respectively.
2. Undetectable levels (< 10 IU/mL) in 8/9 patients in the 75 mg group and 7/10 in the 200 mg group was observed after 4 weeks of treatment with triple therapy.
3. After 12 weeks (4 weeks triple + 8 weeks SoC), 6/9, 9/9 and 10/10 had undetectable virus (< 10 IU/mL) in the 25mg, 75 and 200 mg groups, respectively.
4. No breakthroughs observed after 4 weeks of triple therapy in any of the groups (25, 75 or 200 mg).
5. No treatment related discontinuations, most AEs were mild to moderate.
6. No evidence of TMC related hepatic, renal, CV or blood (haematopoietic) adverse events.
7. Mild and reversible increases in bilirubin observed in highest dose groups (200 mg).
8. Substantial decreases of liver transaminases were observed.
TMC435 in patients that failed previous IFN-based treatment The results from 75, 150 and 200mg are summarized below:
1. Potent, dose-dependent, antiviral activity after 4 weeks treatment with triple therapy with 4.3, 5.5 and 5.3 log 10 IU/mL reduction for 75, 150 and 200 mg QD groups, respectively, compared to 1.5 in the placebo group
2. Three viral breakthroughs were observed in prior non-responders with G1b, 2 in 75 mg and 1 in the 150 mg QD group.
3. At Day 28, 4/9 (44%), 7/9 (78%) and 7/10 (70%) patients achieved plasma HCV RNA levels <25 IU/mL in the 75, 150 and 200 mg QD treatment groups, respectively, compared with no patients (0/9) in the placebo group
4. 2/9 (22%), 5/9 (56%) and 3/10 (30%) patients in 75, 150 and the 200 mg groups reached undetectable levels (< 10 IU/mL) after 4 weeks of treatment, compared to 0/9 patients on placebo.
5. There were no serious adverse events and no treatment discontinuations due to adverse events, which generally were of mild to moderate grade.
6. Liver enzymes were reduced by TMC treatment.
7. Bilirubin increases were observed in some patients on TMC, mostly with the 200 mg group. These elevations were reversible and generally mild.
Conclusions:
In treatment-naïve patients infected with HCV genotype-1, TMC435 in combination with SoC over 4 weeks of treatment:
- demonstrated potent antiviral activity
- was generally safe and well tolerated
- was not associated with AE-related treatment discontinuations
These results support the development of TMC435 for treatment-naïve patients infected with HCV genotype-1.
In treatment experienced patients infected with HCV genotype 1, 28 days of once-daily treatment with TMC435 (75, 150 and 200 mg) as part of a triple therapy regimen with PEGIFN-2a and RBV:
- demonstrated potent, dose-dependent antiviral activity.
- was generally safe and well tolerated.
- was not associated with AE-related treatment discontinuations.
About hepatitis C
According to the World Health Organization, about 170 million people around the world are infected with chronic HCV and 3 to 4 million people are newly infected each year Chronic infection with HCV can lead to cirrhosis and liver cancer, and is the most common cause of liver transplant in Europe.
For more information on Medivir, please see the company website:http://www.medivir.se
Metabolic Syndrome Hikes Mortality in Hepatitis C
Metabolic Syndrome Hikes Mortality in Hepatitis C
By John Gever, Senior Editor, MedPage Today
Published: April 24, 2009
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco Earn CME/CE credit
for reading medical news
WHEELING, W.Va., April 24 -- Patients with hepatitis C infection appear more likely to die from the condition if they also suffer from one or more components of metabolic syndrome, a researcher said.
Excess body weight and hypertension both significantly heightened the risk of liver-related mortality in hepatitis C patients, according to data from the third National Health and Nutrition Examination Survey (NHANES) series, reported Zobair Younossi, M.D., of Inova Health System in Falls Church, Va.
Those two factors as well as the third component of metabolic syndrome -- type 2 diabetes -- also made death from all causes more likely during the study period, said Dr. Younossi.
He spoke with MedPage Today by telephone from Copenhagen, Denmark, in advance of his formal presentation of the data at the annual meeting of the European Association for the Study of the Liver.
Action Points
■Explain to interested patients that progression of hepatitis C is influenced by a variety of factors and comorbid conditions,
■Explain that the study did not address the effects of treatment of hypertension, obesity, or diabetes or insulin resistance on survival of HCV-infected patients.
Earlier research had found numerous factors associated with more rapid progression of hepatitis C infection, Dr. Younossi said, including components of metabolic syndrome individually and, perhaps, together.
To explore the relationship, Dr. Younossi and his colleagues analyzed data from NHANES III, conducted from 1988 to 1994. The data also include mortality follow-up information through 2000, a median of 8.5 years.
Out of more than 31,000 NHANES participants, the researchers identified 264 with hepatitis C and 13,004 without liver disease who could serve as controls.
Only survey participants with complete records for numerous clinical parameters were eligible for inclusion in the study.
The researchers found that hepatitis C cases were more likely than controls to have insulin resistance, as defined by a HOMA score of at least 3 -- 37.4% of cases versus 22.5% of controls (P=0.02) -- and were dramatically more likely to smoke (64.0% versus 26.6%,P<0.001).
A diagnosis of type 2 diabetes was moderately more common among cases as well.
On the other hand, the hepatitis C cases showed somewhat lower rates of hypertension, obesity, and metabolic syndrome.
But the 51 deaths among the hepatitis C cases were disproportionately concentrated in those with the latter conditions.
With multivariate analysis, the researchers calculated the following adjusted hazard ratios for all-cause mortality in hepatitis C cases, compared with controls:
•Type 2 diabetes: HR 2.14 (95% CI 2.11 to 2.16)
•Higher body mass index: HR 1.05 (95% 1.05 to 1.06)
•Hypertension: HR 1.41 (95% CI 1.39 to 1.42)
For liver-related death only, two of these three factors were also strong predictors in the hepatitis C cases:
•Higher BMI: HR 1.28 (95% CI 1.27 to 1.28)
•Hypertension: HR 3.75 (95% CI 3.65 to 3.85)
Dr. Younossi said that patients with any of the components of metabolic syndrome should be treated for them, and those with hepatitis C are no exception.
But he cautioned that only a prospective trial could confirm that successful treatment of metabolic syndrome or its components would improve survival in hepatitis C patients.
He also noted several limitations of the study: lack of liver biopsy or genotype data for hepatitis C cases, a relatively short follow-up, and the potential underestimation of hepatitis C prevalence in NHANES data.
No external funding for the study was reported.
Dr. Younossi reported no potential conflicts of interest.
Primary source: European Association for the Study of the Liver
Source reference:
Rafiq, N. et al "Type 2 diabetes, obesity and hypertension are associated with mortality in hepatitis C patients" EASL 2009; Abstract 324.
By John Gever, Senior Editor, MedPage Today
Published: April 24, 2009
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco Earn CME/CE credit
for reading medical news
WHEELING, W.Va., April 24 -- Patients with hepatitis C infection appear more likely to die from the condition if they also suffer from one or more components of metabolic syndrome, a researcher said.
Excess body weight and hypertension both significantly heightened the risk of liver-related mortality in hepatitis C patients, according to data from the third National Health and Nutrition Examination Survey (NHANES) series, reported Zobair Younossi, M.D., of Inova Health System in Falls Church, Va.
Those two factors as well as the third component of metabolic syndrome -- type 2 diabetes -- also made death from all causes more likely during the study period, said Dr. Younossi.
He spoke with MedPage Today by telephone from Copenhagen, Denmark, in advance of his formal presentation of the data at the annual meeting of the European Association for the Study of the Liver.
Action Points
■Explain to interested patients that progression of hepatitis C is influenced by a variety of factors and comorbid conditions,
■Explain that the study did not address the effects of treatment of hypertension, obesity, or diabetes or insulin resistance on survival of HCV-infected patients.
Earlier research had found numerous factors associated with more rapid progression of hepatitis C infection, Dr. Younossi said, including components of metabolic syndrome individually and, perhaps, together.
To explore the relationship, Dr. Younossi and his colleagues analyzed data from NHANES III, conducted from 1988 to 1994. The data also include mortality follow-up information through 2000, a median of 8.5 years.
Out of more than 31,000 NHANES participants, the researchers identified 264 with hepatitis C and 13,004 without liver disease who could serve as controls.
Only survey participants with complete records for numerous clinical parameters were eligible for inclusion in the study.
The researchers found that hepatitis C cases were more likely than controls to have insulin resistance, as defined by a HOMA score of at least 3 -- 37.4% of cases versus 22.5% of controls (P=0.02) -- and were dramatically more likely to smoke (64.0% versus 26.6%,P<0.001).
A diagnosis of type 2 diabetes was moderately more common among cases as well.
On the other hand, the hepatitis C cases showed somewhat lower rates of hypertension, obesity, and metabolic syndrome.
But the 51 deaths among the hepatitis C cases were disproportionately concentrated in those with the latter conditions.
With multivariate analysis, the researchers calculated the following adjusted hazard ratios for all-cause mortality in hepatitis C cases, compared with controls:
•Type 2 diabetes: HR 2.14 (95% CI 2.11 to 2.16)
•Higher body mass index: HR 1.05 (95% 1.05 to 1.06)
•Hypertension: HR 1.41 (95% CI 1.39 to 1.42)
For liver-related death only, two of these three factors were also strong predictors in the hepatitis C cases:
•Higher BMI: HR 1.28 (95% CI 1.27 to 1.28)
•Hypertension: HR 3.75 (95% CI 3.65 to 3.85)
Dr. Younossi said that patients with any of the components of metabolic syndrome should be treated for them, and those with hepatitis C are no exception.
But he cautioned that only a prospective trial could confirm that successful treatment of metabolic syndrome or its components would improve survival in hepatitis C patients.
He also noted several limitations of the study: lack of liver biopsy or genotype data for hepatitis C cases, a relatively short follow-up, and the potential underestimation of hepatitis C prevalence in NHANES data.
No external funding for the study was reported.
Dr. Younossi reported no potential conflicts of interest.
Primary source: European Association for the Study of the Liver
Source reference:
Rafiq, N. et al "Type 2 diabetes, obesity and hypertension are associated with mortality in hepatitis C patients" EASL 2009; Abstract 324.
Avila Therapeutics May Have Found “Achilles’ Heel” of Hepatitis C Virus
"AVL-181 has broad activity across HCV-P genotypes and is active on drug-resistant mutations in the cellular replicon assay. However, AVL-181 maintains selectivity for the HCV-P and does not have any appreciable activity on host proteases. AVL-181 has a rapid onset of inhibition (< 1hr) in a direct in vitro assay of HCV-P activity against WT and drug-resistant mutations and this activity is prolonged for greater than 24 hours."
Avila Therapeutics May Have Found “Achilles’ Heel” of Hepatitis C Virus
Ryan McBride 4/27/09 http://www.xconomy.com
Avila Therapeutics emerged from stealth mode in December and told Xconomy about its secret sauce to systematically create permanent, covalent bonds with protein disease targets. Now the Waltham, MA-based biotech (pronounced AH-vill-uh) reports that its experimental drug for hepatitis C virus may be able to wipe out multiple variations and mutated forms of the virus.
The firm’s drug, dubbed AVL-181, is a small molecule protease inhibitor intended to silence a key protein for the survival and replication of the virus. The drug targets a region of the protein that the company believes is common among many known forms of the virus, even those that are resistant to standard treatments, meaning that the firm may have found an “Achilles’ heel” of the protein, says Nagesh Mahanthappa, vice president of business development and operations at the biotech. Over the weekend, the company presented results of a study, in which infected mice were treated with the drug, at the European Association for the Study of the Liver meeting in Copenhagen, Denmark.
“When we look across all known published genetic sequences of the hepatitis C protease, from a variety of mutants, we find that the particular site where we get bond formation with our drug is constant,” Mahanthappa says. “It remains possible that that site is somehow critical for the protease’s normal function, or the general fitness of the virus.”
It’s early in the game to draw any conclusions about Avila’s hepatitis C drug, which to date hasn’t yet advanced to clinical trials. Yet the fact that the startup may have found a new weakness in the virus, making the drug effective across drug-resistant and mutated strains, could help the drug stand out among the 40-odd other hepatitis C treatments in development. With industry embracing a cocktail approach to treating the disease, Mahanthappa says, there’s a possibility that Avila’s drug could be useful in combination with other drugs to combat difficult-to-treat variations of hepatitis C, which is a chronic liver disease that affects 170 million people worldwide.
The study presented over the weekend showed several potential benefits of Avila’s hepatitis C drug over existing treatments. For one, it had no significant impact on other proteins, boding well for how safe the drug could be for humans. Another potential perk is that the drug appears to work for 24 hours or more, meaning it could be taken once a day rather than several times a day. Yet there were many new hepatitis C drugs presented at the medical conference and most of the companies presenting those other drugs promised improvements over existing therapies as well. Cambridge, MA-based Vertex Pharmaceuticals (NASDAQ: VRTX) is generally considered the front-runner in the race to develop the first protease inhibitor for hepatitis C, called telaprevir. That drug is now in the third and final stage of clinical trials needed before it can win FDA approval to start selling in the U.S.
For Avila, the hepatitis C protease inhibitor is one of two drugs that are neck and neck for top position in the biotech’s young pipeline, Mahanthappa says. The other, called AVL-291, is a small molecule kinase inhibitor that could be used to treat immune system cancers such as non-Hodgkin’s lymphoma and B cell chronic lymphocytic leukemia. The company’s earlier plan was to begin human clinical trials of its hepatitis C drug by late 2009, but Mahanthappa says that the company now wants to wait until mid-2010 to start its first clinical trial. The company also hasn’t decided which of its drugs to enter into clinical trials first. The reason for waiting an extra half year to begin clinical trials is to make the firm’s existing capital last longer. The firm wants to raise more venture capital before it launches an initial clinical trial and—in case you’ve been living under a rock and don’t know—the climate nowadays for completing such financings is pretty awful.
Avila is now in the midst of raising another round of financing, Mahanthappa says. The firm has previously recieved $21 million in venture capital from lead investor Abingworth Management as well as Polaris Venture Partners, Atlas Venture, and Advent Venture Partners.
Presentation Date: Apr 25, 2009
PROTEIN SILENCING OF HEPATITIS C VIRUS PROTEASE WITH A SMALL MOLECULE INHIBITOR: DISCOVERY OF AVL-181
D. Niu, M. Hagel, H. Bernard, L. Qiao, M. Nacht, R. Petter, M. Sheets, J. Singh, T.S. Martin, W. Westlin
Avila Therapeutics, Inc., Waltham, MA, USA
Aim: Investigational drugs that target the NS3 protease of hepatitis C virus (HCV-P) require frequent dosing due to limited oral availability and short circulating half-life. In addition, drug-resistant mutations arise due to reduced potency of these agents for the mutated proteases. AVL-181 is the first experimental agent in a new paradigm for the treatment of HCV that has the potential to overcome the clinical liabilities of previous investigational HCV-P inhibitors.
Results: AVL-181, a novel small molecule inhibitor of HCV-P, directly bonds the HCV-P protein through covalent modification of a specific non-catalytic residue in the active site leading to rapid, complete and prolonged silencing of protease activity. AVL-181 is a potent inhibitor of wild-type (WT) HCV-P in biochemical (IC50= 0.4nM) and replicon cellular (EC50= 4.6nM) in vitro assays. Time-dependent inactivation of the HCV-P leads to potent activity on several drug-resistant mutations. Moreover, AVL-181 has broad activity across HCV-P genotypes and is active on drug-resistant mutations in the cellular replicon assay. However, AVL-181 maintains selectivity for the HCV-P and does not have any appreciable activity on host proteases. AVL-181 has a rapid onset of inhibition (< 1hr) in a direct in vitro assay of HCV-P activity against WT and drug-resistant mutations and this activity is prolonged for greater than 24 hours. Due to the rapid and complete protein silencing of the HCV-P by AVL-181, the functional half-life of this novel inhibitor is dependent on protein turnover rather than on continuous exposure to drug. The prolonged pharmacodynamic activity of AVL-181, coupled with significant oral bioavailability (~30% in rat), suggests this compound has the potential for once daily oral administration.
Conclusion: Using a new paradigm in the design of inhibitors of hepatitis C virus protease, we have discovered a novel compound with the ability to rapidly and completely silence the HCV protease through covalent bonding of the protein. AVL-181 is a potent inhibitor of wild-type and drug resistant HCV protease mutations with pharmacokinetic and pharmacodynamic properties to enable once daily oral dosing. Clinical investigation of AVL-181 is anticipated to begin in 2009.
Avila Therapeutics May Have Found “Achilles’ Heel” of Hepatitis C Virus
Ryan McBride 4/27/09 http://www.xconomy.com
Avila Therapeutics emerged from stealth mode in December and told Xconomy about its secret sauce to systematically create permanent, covalent bonds with protein disease targets. Now the Waltham, MA-based biotech (pronounced AH-vill-uh) reports that its experimental drug for hepatitis C virus may be able to wipe out multiple variations and mutated forms of the virus.
The firm’s drug, dubbed AVL-181, is a small molecule protease inhibitor intended to silence a key protein for the survival and replication of the virus. The drug targets a region of the protein that the company believes is common among many known forms of the virus, even those that are resistant to standard treatments, meaning that the firm may have found an “Achilles’ heel” of the protein, says Nagesh Mahanthappa, vice president of business development and operations at the biotech. Over the weekend, the company presented results of a study, in which infected mice were treated with the drug, at the European Association for the Study of the Liver meeting in Copenhagen, Denmark.
“When we look across all known published genetic sequences of the hepatitis C protease, from a variety of mutants, we find that the particular site where we get bond formation with our drug is constant,” Mahanthappa says. “It remains possible that that site is somehow critical for the protease’s normal function, or the general fitness of the virus.”
It’s early in the game to draw any conclusions about Avila’s hepatitis C drug, which to date hasn’t yet advanced to clinical trials. Yet the fact that the startup may have found a new weakness in the virus, making the drug effective across drug-resistant and mutated strains, could help the drug stand out among the 40-odd other hepatitis C treatments in development. With industry embracing a cocktail approach to treating the disease, Mahanthappa says, there’s a possibility that Avila’s drug could be useful in combination with other drugs to combat difficult-to-treat variations of hepatitis C, which is a chronic liver disease that affects 170 million people worldwide.
The study presented over the weekend showed several potential benefits of Avila’s hepatitis C drug over existing treatments. For one, it had no significant impact on other proteins, boding well for how safe the drug could be for humans. Another potential perk is that the drug appears to work for 24 hours or more, meaning it could be taken once a day rather than several times a day. Yet there were many new hepatitis C drugs presented at the medical conference and most of the companies presenting those other drugs promised improvements over existing therapies as well. Cambridge, MA-based Vertex Pharmaceuticals (NASDAQ: VRTX) is generally considered the front-runner in the race to develop the first protease inhibitor for hepatitis C, called telaprevir. That drug is now in the third and final stage of clinical trials needed before it can win FDA approval to start selling in the U.S.
For Avila, the hepatitis C protease inhibitor is one of two drugs that are neck and neck for top position in the biotech’s young pipeline, Mahanthappa says. The other, called AVL-291, is a small molecule kinase inhibitor that could be used to treat immune system cancers such as non-Hodgkin’s lymphoma and B cell chronic lymphocytic leukemia. The company’s earlier plan was to begin human clinical trials of its hepatitis C drug by late 2009, but Mahanthappa says that the company now wants to wait until mid-2010 to start its first clinical trial. The company also hasn’t decided which of its drugs to enter into clinical trials first. The reason for waiting an extra half year to begin clinical trials is to make the firm’s existing capital last longer. The firm wants to raise more venture capital before it launches an initial clinical trial and—in case you’ve been living under a rock and don’t know—the climate nowadays for completing such financings is pretty awful.
Avila is now in the midst of raising another round of financing, Mahanthappa says. The firm has previously recieved $21 million in venture capital from lead investor Abingworth Management as well as Polaris Venture Partners, Atlas Venture, and Advent Venture Partners.
Presentation Date: Apr 25, 2009
PROTEIN SILENCING OF HEPATITIS C VIRUS PROTEASE WITH A SMALL MOLECULE INHIBITOR: DISCOVERY OF AVL-181
D. Niu, M. Hagel, H. Bernard, L. Qiao, M. Nacht, R. Petter, M. Sheets, J. Singh, T.S. Martin, W. Westlin
Avila Therapeutics, Inc., Waltham, MA, USA
Aim: Investigational drugs that target the NS3 protease of hepatitis C virus (HCV-P) require frequent dosing due to limited oral availability and short circulating half-life. In addition, drug-resistant mutations arise due to reduced potency of these agents for the mutated proteases. AVL-181 is the first experimental agent in a new paradigm for the treatment of HCV that has the potential to overcome the clinical liabilities of previous investigational HCV-P inhibitors.
Results: AVL-181, a novel small molecule inhibitor of HCV-P, directly bonds the HCV-P protein through covalent modification of a specific non-catalytic residue in the active site leading to rapid, complete and prolonged silencing of protease activity. AVL-181 is a potent inhibitor of wild-type (WT) HCV-P in biochemical (IC50= 0.4nM) and replicon cellular (EC50= 4.6nM) in vitro assays. Time-dependent inactivation of the HCV-P leads to potent activity on several drug-resistant mutations. Moreover, AVL-181 has broad activity across HCV-P genotypes and is active on drug-resistant mutations in the cellular replicon assay. However, AVL-181 maintains selectivity for the HCV-P and does not have any appreciable activity on host proteases. AVL-181 has a rapid onset of inhibition (< 1hr) in a direct in vitro assay of HCV-P activity against WT and drug-resistant mutations and this activity is prolonged for greater than 24 hours. Due to the rapid and complete protein silencing of the HCV-P by AVL-181, the functional half-life of this novel inhibitor is dependent on protein turnover rather than on continuous exposure to drug. The prolonged pharmacodynamic activity of AVL-181, coupled with significant oral bioavailability (~30% in rat), suggests this compound has the potential for once daily oral administration.
Conclusion: Using a new paradigm in the design of inhibitors of hepatitis C virus protease, we have discovered a novel compound with the ability to rapidly and completely silence the HCV protease through covalent bonding of the protein. AVL-181 is a potent inhibitor of wild-type and drug resistant HCV protease mutations with pharmacokinetic and pharmacodynamic properties to enable once daily oral dosing. Clinical investigation of AVL-181 is anticipated to begin in 2009.
Hepatitis C Therapeutic Vaccine, GI-5005, Improves EVR Rates to 94 Percent in Phase 2
GlobeImmune's Hepatitis C Therapeutic Vaccine, GI-5005, Improves EVR Rates to 94 Percent in Phase 2
Poster Presentations
Presentation Date: Apr 24, 2009
GI-5005 IMMUNOTHERAPY PLUS PEG-IFN/RIBAVIRIN VERSUS PEG-IFN/RIBAVIRIN IN GENOTYPE 1 CHRONIC HCV SUBJECTS; PRELIMINARY PHASE 2 EVR ANALYSES
E.J. Lawitz1, T.D. Boyer2, G.T. Everson3, I.M. Jacobson4, W. Lee5, J.G. McHutchison6, P.J. Pockros7, M.L. Shiffman8, J.M. Vierling9, S. Cruickshank10, T.C. Rodell11, D. Apelian11
1Alamo Medical Research, San Antonio, TX, 2University of Arizona, Tucson, AZ, 3Department of Medicine, University of Colorado Denver, Aurora, CO, 4Department of Medicine, Weill Cornell Medical College, New York, NY, 5Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 6Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, 7The Scripps Clinical Research Center, La Jolla, CA, 8Hepatology Section, Virginia Commonwealth University Medical Center, Richmond, VA, 9Department of Medicine and Surgery, Baylor College of Medicine, Houston, TX, 10Cruickshank and Associates, Santa Barbara, CA, 11GlobeImmune, Inc., Louisville, CO, USA
Background and aims: GI-5005 is a whole heat-killed S. cerevisiae immunotherapy expressing HCV NS3 and Core antigens. GI-5005 has been designed to elicit antigen-specific T-cell responses with the goal of improving the rate of immune clearance of HCV. HCV genotype 1 patients enrolled in a trial comparing pegylated interferon plus ribavirin with and without GI-5005 were compared in a prior interim analysis; RVRs for triple therapy compared to SOC alone were >2 fold more frequent (Hepatology 2008; 48: 1023A). Interim EVR data are presented here.
Methods: Naïve and non-responder chronic HCV genotype 1 patients were eligible (null responders and relapsers were excluded), and were randomized 1:1 and stratified by prior virologic response in this open label trial; Arm 1- GI-5005 monotherapy run-in consisting of five weekly followed by 2 monthly subcutaneous (SC) doses of 40YU (1 YU = 10,000,000 yeast) GI-5005 over 12 weeks, followed by triple therapy consisting of monthly 40YU GI-5005 doses plus 48 weeks pegIFN/ribavirin (SOC), Arm 2- SOC alone.
Results: At this time, 52/72 triple therapy subjects and 65/68 SOC subjects were evaluable for EVR (≥ 2 log10 reduction in HCV RNA at week 12, with last observation carried forward). Triple therapy showed a trend for improved EVR in all naïve subjects (34/36 {94.4%} vs. 40/46 {87%} p=0.23) and naïve subjects with high baseline viral load (>600,000IU/mL) (28/30 {93.3%} vs. 35/41 {85.4%} p=0.26). EVR was comparable for triple therapy and SOC in the small subset of prior non-responder subjects. GI-5005 has been well-tolerated, with no GI-5005 related serious adverse events or dose limiting toxicities to date.
Conclusions: Triple therapy with GI-5005 plus pegIFN/ribavirin was well tolerated and preliminary data indicate improved EVR rates, despite an unusually high EVR rate in the SOC group. These data are consistent with the HCV-specific cellular immune responses observed in the GI-5005-01 phase 1 trial and the improved week 4 RVR in the current trial. This therapeutic approach and the mechanism of GI-5005 support further investigation and development of combination therapy strategies in chronic HCV infection. Complete cohort data for naives and non-responders will be included at the time of presentation.
Monday, 27 April 2009
http://pr-canada.net
Twelve-week Phase 2 clinical trial data show that patients treated with GI-5005, GlobeImmune's targeted molecular immunogen (Tarmogen®) for the treatment of hepatitis C virus infection, had 94 percent early virologic response (EVR) rate in treatment naïve patients. The study compared GI-5005 plus standard of care (SOC) -- pegylated interferon and ribavirin -- versus SOC alone in patients with chronic genotype 1 hepatitis C infection.
The study data will be presented in a poster presentation tomorrow by Eric Lawitz, M.D., of Alamo Medical Research Center, San Antonio, Tex. at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL) in Copenhagen, Denmark. The 94 percent EVR rate in naïve subgroups including those with high baseline viral loads, is defined as a greater than 100-fold reduction of HCV RNA from baseline at 12 weeks and is an eight to twelve percent improvement over the SOC alone arm.
"We were pleased to see a 94 percent EVR rate in the treatment naïve patient population," said Dr. Lawitz, the study's lead author. "We believe that this increase in EVR over standard of care alone may indicate that the GI-5005 mechanism of action is complementary to the current standard care."
Additional exploratory analyses of serum fibrosis (Fibrotest) and necrosis (Actitest) markers showed a two-fold improvement in the proportion of patients with improved serum Fibrotest, and a fifty percent reduction in the number of patients with worsening Fibrotest scores after 24 weeks in the group receiving the triple therapy. At the 24 week time point, the triple therapy improved serum Actitest scores by up to 14 percent in treatment naïve patients when compared to SOC alone. The treatment naïve group with high viral load receiving the triple therapy also saw a 14 percent advantage over the SOC group in normalization of alanine transaminase (ALT), a marker of liver damage.
"We believe that the improvement in ALT, Actitest and Fibrotest scores seen in patients in the triple therapy arm of the study suggests that triple therapy with GI-5005 may lead to improvements in liver inflammation, necrosis and fibrosis compared to standard of care alone," said David Apelian, M.D., Ph.D., GlobeImmune's Chief Medical Officer. "At this interim stage of our Phase 2 program, we are encouraged by the data as we believe they suggest that triple therapy including GI-5005 may improve sustained virologic response as well as liver histology, both of which will be measured in the current study and could serve as primary or co-primary efficacy endpoints in a future Phase 3 HCV program."
The GI-5005-02 clinical trial is a randomized, multi-center, Phase 2 study evaluating 140 patients, all with genotype 1 HCV infection. In the trial, 74 percent of patients had never received prior treatment, and the remaining 26 percent had failed prior treatment.
About GlobeImmune
GlobeImmune Inc. is a private company developing targeted molecular immunogens, Tarmogens, for the treatment of cancer and infectious diseases. The company's lead product candidate, GI-5005, is a Tarmogen for the treatment of chronic hepatitis C infection (HCV). GI-5005 is designed to complement both the current standard of care and emerging novel therapies for HCV. The company's lead oncology program, GI-4000, targets cancers caused by mutated versions of the Ras oncoprotein. GI-4000 is being investigated in clinical trials for the treatment of pancreas cancer as well as other cancers that contain mutated Ras, including non-small cell lung cancer and colorectal cancer.
For additional information, please visit the company's Web site at www.globeimmune.com.
This news release and the anticipated presentation contain forward-looking statements that involve risks and uncertainties, including statements relating to initiation and progress of the Company's clinical trial programs and the preliminary results from the clinical trials. Actual results could differ materially from those projected and the Company cautions readers not to place undue reliance on the forward-looking statements contained in the release and anticipated presentation.
Poster Presentations
Presentation Date: Apr 24, 2009
GI-5005 IMMUNOTHERAPY PLUS PEG-IFN/RIBAVIRIN VERSUS PEG-IFN/RIBAVIRIN IN GENOTYPE 1 CHRONIC HCV SUBJECTS; PRELIMINARY PHASE 2 EVR ANALYSES
E.J. Lawitz1, T.D. Boyer2, G.T. Everson3, I.M. Jacobson4, W. Lee5, J.G. McHutchison6, P.J. Pockros7, M.L. Shiffman8, J.M. Vierling9, S. Cruickshank10, T.C. Rodell11, D. Apelian11
1Alamo Medical Research, San Antonio, TX, 2University of Arizona, Tucson, AZ, 3Department of Medicine, University of Colorado Denver, Aurora, CO, 4Department of Medicine, Weill Cornell Medical College, New York, NY, 5Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 6Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, 7The Scripps Clinical Research Center, La Jolla, CA, 8Hepatology Section, Virginia Commonwealth University Medical Center, Richmond, VA, 9Department of Medicine and Surgery, Baylor College of Medicine, Houston, TX, 10Cruickshank and Associates, Santa Barbara, CA, 11GlobeImmune, Inc., Louisville, CO, USA
Background and aims: GI-5005 is a whole heat-killed S. cerevisiae immunotherapy expressing HCV NS3 and Core antigens. GI-5005 has been designed to elicit antigen-specific T-cell responses with the goal of improving the rate of immune clearance of HCV. HCV genotype 1 patients enrolled in a trial comparing pegylated interferon plus ribavirin with and without GI-5005 were compared in a prior interim analysis; RVRs for triple therapy compared to SOC alone were >2 fold more frequent (Hepatology 2008; 48: 1023A). Interim EVR data are presented here.
Methods: Naïve and non-responder chronic HCV genotype 1 patients were eligible (null responders and relapsers were excluded), and were randomized 1:1 and stratified by prior virologic response in this open label trial; Arm 1- GI-5005 monotherapy run-in consisting of five weekly followed by 2 monthly subcutaneous (SC) doses of 40YU (1 YU = 10,000,000 yeast) GI-5005 over 12 weeks, followed by triple therapy consisting of monthly 40YU GI-5005 doses plus 48 weeks pegIFN/ribavirin (SOC), Arm 2- SOC alone.
Results: At this time, 52/72 triple therapy subjects and 65/68 SOC subjects were evaluable for EVR (≥ 2 log10 reduction in HCV RNA at week 12, with last observation carried forward). Triple therapy showed a trend for improved EVR in all naïve subjects (34/36 {94.4%} vs. 40/46 {87%} p=0.23) and naïve subjects with high baseline viral load (>600,000IU/mL) (28/30 {93.3%} vs. 35/41 {85.4%} p=0.26). EVR was comparable for triple therapy and SOC in the small subset of prior non-responder subjects. GI-5005 has been well-tolerated, with no GI-5005 related serious adverse events or dose limiting toxicities to date.
Conclusions: Triple therapy with GI-5005 plus pegIFN/ribavirin was well tolerated and preliminary data indicate improved EVR rates, despite an unusually high EVR rate in the SOC group. These data are consistent with the HCV-specific cellular immune responses observed in the GI-5005-01 phase 1 trial and the improved week 4 RVR in the current trial. This therapeutic approach and the mechanism of GI-5005 support further investigation and development of combination therapy strategies in chronic HCV infection. Complete cohort data for naives and non-responders will be included at the time of presentation.
Monday, 27 April 2009
http://pr-canada.net
Twelve-week Phase 2 clinical trial data show that patients treated with GI-5005, GlobeImmune's targeted molecular immunogen (Tarmogen®) for the treatment of hepatitis C virus infection, had 94 percent early virologic response (EVR) rate in treatment naïve patients. The study compared GI-5005 plus standard of care (SOC) -- pegylated interferon and ribavirin -- versus SOC alone in patients with chronic genotype 1 hepatitis C infection.
The study data will be presented in a poster presentation tomorrow by Eric Lawitz, M.D., of Alamo Medical Research Center, San Antonio, Tex. at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL) in Copenhagen, Denmark. The 94 percent EVR rate in naïve subgroups including those with high baseline viral loads, is defined as a greater than 100-fold reduction of HCV RNA from baseline at 12 weeks and is an eight to twelve percent improvement over the SOC alone arm.
"We were pleased to see a 94 percent EVR rate in the treatment naïve patient population," said Dr. Lawitz, the study's lead author. "We believe that this increase in EVR over standard of care alone may indicate that the GI-5005 mechanism of action is complementary to the current standard care."
Additional exploratory analyses of serum fibrosis (Fibrotest) and necrosis (Actitest) markers showed a two-fold improvement in the proportion of patients with improved serum Fibrotest, and a fifty percent reduction in the number of patients with worsening Fibrotest scores after 24 weeks in the group receiving the triple therapy. At the 24 week time point, the triple therapy improved serum Actitest scores by up to 14 percent in treatment naïve patients when compared to SOC alone. The treatment naïve group with high viral load receiving the triple therapy also saw a 14 percent advantage over the SOC group in normalization of alanine transaminase (ALT), a marker of liver damage.
"We believe that the improvement in ALT, Actitest and Fibrotest scores seen in patients in the triple therapy arm of the study suggests that triple therapy with GI-5005 may lead to improvements in liver inflammation, necrosis and fibrosis compared to standard of care alone," said David Apelian, M.D., Ph.D., GlobeImmune's Chief Medical Officer. "At this interim stage of our Phase 2 program, we are encouraged by the data as we believe they suggest that triple therapy including GI-5005 may improve sustained virologic response as well as liver histology, both of which will be measured in the current study and could serve as primary or co-primary efficacy endpoints in a future Phase 3 HCV program."
The GI-5005-02 clinical trial is a randomized, multi-center, Phase 2 study evaluating 140 patients, all with genotype 1 HCV infection. In the trial, 74 percent of patients had never received prior treatment, and the remaining 26 percent had failed prior treatment.
About GlobeImmune
GlobeImmune Inc. is a private company developing targeted molecular immunogens, Tarmogens, for the treatment of cancer and infectious diseases. The company's lead product candidate, GI-5005, is a Tarmogen for the treatment of chronic hepatitis C infection (HCV). GI-5005 is designed to complement both the current standard of care and emerging novel therapies for HCV. The company's lead oncology program, GI-4000, targets cancers caused by mutated versions of the Ras oncoprotein. GI-4000 is being investigated in clinical trials for the treatment of pancreas cancer as well as other cancers that contain mutated Ras, including non-small cell lung cancer and colorectal cancer.
For additional information, please visit the company's Web site at www.globeimmune.com.
This news release and the anticipated presentation contain forward-looking statements that involve risks and uncertainties, including statements relating to initiation and progress of the Company's clinical trial programs and the preliminary results from the clinical trials. Actual results could differ materially from those projected and the Company cautions readers not to place undue reliance on the forward-looking statements contained in the release and anticipated presentation.
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