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Albuferon
January 28th, 2003
Albuferon-alpha Well Tolerated, Has Prolonged Half-Life
Immunotherapy Weekly
Human Genome Sciences, Inc., (HGSI) presented the results of 3 phase I clinical trials of its new drugs to an audience of financial analysts and investors at the 21st Annual JP Morgan H & Q Healthcare Conference in San Francisco.
Results were reported for phase I clinical trials of Albuferon-alpha in adults with hepatitis C, and of BLyS in patients with common variable immunodeficiency (CVID). The company also discussed previously disclosed results of a phase I clinical trial of Albutropin in adults with growth hormone deficiency, and provided an update on the progress of other drugs in Human Genome Sciences' clinical development pipeline.
During its presentation to the 21st Annual JP Morgan H & Q Healthcare Conference, Human Genome Sciences presented the following data:
Albuferon-alpha phase I clinical trial results:
Results from a phase I clinical trial of Albuferon-alpha, the company's novel long-acting form of interferon alpha, demonstrate that Albuferon-alpha is well tolerated, has a prolonged half-life, and is biologically active in adults with chronic hepatitis C. Forty-one patients have been treated in the multicenter, open-label, dose-escalation study.
The primary purpose of the phase I clinical trial is to determine the safety, tolerability and pharmacokinetics of Albuferon-alpha in adults with chronic hepatitis C who have failed previous interferon alpha treatments. Pharmacodynamics, immunogenicity, and biological activity data also were evaluated. Ninety-three percent of the patients (38 of 41) participating in the trial were infected with hepatitis C virus (HCV) genotype 1, which accounts for nearly 70% of all HCV infections in the United States and is generally regarded as the most difficult HCV genotype to treat.
On average, patients participating in the study had been treated previously for approximately 12 months with interferon alpha or pegylated interferon alpha, either alone or in combination with ribavirin. The protocol called for patients to be given either single doses of Albuferon-alpha subcutaneously, or 2 doses of Albuferon-alpha subcutaneously 14 days apart, at 7 micrograms (microg), 20 microg, 40 microg, or 80 microg.
Results show that Albuferon-alpha is well tolerated, has a prolonged half-life, and is biologically active in adults with chronic hepatitis C. There were no drug-related serious adverse events or discontinuations. Albuferon-alpha remains in the blood substantially longer than is reported for recombinant interferon alpha and pegylated interferon alpha. At 80 microg, Albuferon-alpha exhibited a mean half-life of up to 157 hours. This compares to a half-life of 70 to 90 hours reported for Pegasys, and a half-life of 35 to 40 hours reported for Peg-Intron. No patient developed an immune response against Albuferon-alpha.
The level of the enzyme known as 2', 5'-oligoadenylate synthetase (OAS) in peripheral blood cells is a biological marker for the activity of interferon alpha. Albuferon-alpha was found to be biologically active and capable of inducing prolonged elevations of 2', 5'-oligoadenylate synthetase mRNA. The elevations in 2', 5' OAS mRNA were sustained for up to 28 days following a single injection of Albuferon-alpha. Levels of alanine aminotransferase (ALT), an enzyme, which is elevated by liver cell injury, were reduced substantially in some patients. Furthermore, even at the low doses evaluated, the HCV viral load was reduced in some patients.
Albuferon-alpha was found to be biologically active and capable of inducing prolonged elevations of 2', 5'-oligoadenylate synthetase mRNA. The elevations in 2', 5' OAS mRNA were sustained for up to 28 days following a single injection of Albuferon-alpha.
Interim data on the Albuferon-alpha phase I study were presented at the American Association for the Study of Liver Diseases (AASLD) meeting in November 2002. Human Genome Sciences is continuing to evaluate Albuferon-alpha's safety, tolerability, and pharmacology at higher doses, in single-dose and repeat-dose cohorts, under an amended protocol designed to seek the maximum biological response that can be achieved at a tolerable dose.
BLyS phase I clinical trial results:
A phase I clinical trial to evaluate the safety and pharmacology of BLyS (B-lymphocyte stimulator) in patients with common variable immunodeficiency (CVID) is complete. The primary endpoint of the multicenter, open-label, dose-escalation study was safety. Pharmacokinetics, immunogenicity, and the effects of BLyS on peripheral B cell representation and serum immunoglobulin concentration also were evaluated. Results demonstrate that BLyS is safe and well tolerated. There were no drug-related serious adverse events or discontinuations. BLyS is a novel protein discovered by Human Genome Sciences that stimulates immune system cells called B cells to mature into plasma B cells, which produce antibodies.
BLyS also is the subject of an ongoing phase I clinical trial to evaluate its potential as a treatment for an immune disorder known as immunoglobulin-A (IgA) deficiency. The phase I study in IgA deficiency continues to enroll patients.
Albutropin phase I clinical trial results and next steps:
A phase I clinical trial of Albutropin, Human Genome Sciences' novel long-acting form of human growth hormone, is complete. The primary purpose of the multi-center, open-label, dose-escalating phase I clinical trial was to determine Albutropin's safety and tolerability in adults with growth hormone deficiency. Pharmacodynamic, immunogenicity, and biological activity also were evaluated.
Forty-two patients were given either single doses of Albutropin subcutaneously at 10 microg/kg, 30 microg/kg, or 60 microg/kg, or 2 doses of Albutropin subcutaneously at 60 microg/kg 7 days apart. The results show that Albutropin is biologically active and well tolerated. There were no drug-related serious adverse events or discontinuations. Albutropin remains in the blood substantially longer than is reported for recombinant native human growth hormone. No patient developed an immune response against Albutropin.
The level of insulin-like growth factor-1 (IGF-1) in serum is a robust surrogate marker for the biological activity of human growth hormone. Albutropin was found to be biologically active and capable of restoring IGF-1 levels to within the normal range in a dose-dependent manner. Sixty-four percent of patients (9 of 14) responded who received single doses of Albutropin at 60 microg/kg, and 66% of patients (6 of 9) responded who received 2 doses of Albutropin 7 days apart at 60 microg/kg. Drug responses were defined in the trial as at least a 50% increase over baseline to within the normal range of IGF-1 levels. The IGF-1 responses were durable, lasting from 5 to 6 days following each injection of Albutropin. These data were first reported in October 2002 at a joint meeting of the Growth Hormone Research Society and the International Society for Insulin-like Growth Factor Research.
Phase I results showed that patients who responded to a single 60 microg/kg dose of Albutropin and patients who responded to 2 60 microg/kg doses of Albutropin administered 7 days apart experienced prolonged elevations of IGF-1 to within the normal range. The IGF-1 responses were durable, lasting from 5 to 6 days following each injection of Albutropin. The positive results from this initial phase I study of Albutropin provide Human Genome Sciences with the safety, dosing, and biological activity data needed to support advancing Albutropin into the next phase of clinical development.
ANA245
Chronological Listing of News Reviews and Releases:
March 3rd, 2003
Anadys Reports Completion of Phase IA Study of ANA245
http://www.hcvadvocate.org/news/newsRev
/NewsRev-15.html#22
December 5th, 2003
Anadys Pharmaceuticals Reports Interim Results of Phase 1B
http://www.hcvadvocate.org/news/newsRev
/NewsRev-25.html#12
May 26th, 2004
Anadys Pharmaceuticals Announces Selection of ANA975 As A Development Candidate For Front-Line Treatment Of Chronic Hepatitis C
http://www.hcvadvocate.org/news/newsRev
/2004/NewsRev-50.html
October 14th, 2004
Anadys Pharmaceuticals to Report New Clinical Data from Hepatitis C and Hepatitis B Programs at Upcoming AASLD Annual Meeting
http://www.hcvadvocate.org/news/newsRev
/2004/NewsRev-70.html#9
ANA971
Chronological Listing of News Reviews and Releases:
February 19th, 2004
Anadys Pharmaceuticals Announces Initiation Of Clinical Trial Of ANA971, An Orally Administered Prodrug Of Isatoribine
http://www.hcvadvocate.org/news/newsRev
/2004/NewsRev-36.html#9
May 26th, 2004
Anadys Pharmaceuticals Announces Selection of ANA975 As A Development Candidate For Front-Line Treatment Of Chronic Hepatitis C
"ANA975 was selected from the ANA97X family of isatoribine prodrug compounds based upon its favorable pharmaceutical properties, which we believe should allow it to become an orally administered front-line treatment for chronic HCV," said Devron Averett, Ph.D., Senior Vice President of Drug Development for Anadys.
http://www.hcvadvocate.org/news/newsRev
/2004/NewsRev-50.html#6
IDN-6556
Chronological Listing of News Reviews and Releases:
On May 20th, 2002
Idun Pharmaceuticals announces that IDN-6556, a caspase inhibitor completes Phase 1 clinical trial for HCV
Idun Pharmaceuticals, Inc. presented positive results of its Phase 1 clinical trial of IDN-6556 yesterday at the Digestive Disease Week 2002 conference in San Francisco. The drug was safe and well tolerated in the clinical study involving 76 normal adults and patients with mild liver impairment. Statistically significant and clinically relevant improvements in liver enzymes were seen in the patients with mild liver impairment treated with IDN-6556. These patients included individuals with stable hepatitis C virus (HCV) infection. Idun plans to study IDN-6556 in larger Phase 2 clinical trials in patients with HCV infection and acute alcoholic hepatitis.
IDN-6556 is the first broad-spectrum caspase inhibitor to be studied in humans and acts to preserve the structure and function of cells under stress. The liver damage seen with HCV infection results from the body's defense mechanisms and apoptosis is involved in this process. While IDN-6556 is not an anti-viral drug and will not cure patients of the viral infection, it is thought that treatment of infected patients with IDN-6556 may preserve the cells of the liver and help them to maintain their normal liver function and health.
"There is a considerable and growing need for additional drugs to treat numerous liver diseases. We believe that the protective effects that we have seen with this drug will be useful in several liver diseases," said Dr. David Shapiro, Chief Medical Officer and Executive Vice President at Idun. "Based on the number of people affected, the market potential for this drug is huge and includes hepatitis B virus infection, an enormous medical problem, particularly in Asia."
http://www.hcvadvocate.org/news
/NewsUpdates_pdf/2.1.1.1_
News%20Review_Archive_2002/NewsRev-6.pdf
October 8th, 2003
Idun Pharmaceuticals Initiates Phase 2 Clinical Trial In Liver Transplantation
http://www.hcvadvocate.org/news/newsRev
/NewsRev-23.html#13
October 27th, 2003
Idun Pharmaceuticals Reports Positive Data for First Oral Clinical Trial in HCV Patients
http://www.hcvadvocate.org/news/newsRev
/NewsRev-24.html#36
June 2004 HCV Advocate
Update from DDW: Part 1
Alan Franciscus, Editor-in-Chief
http://www.hcvadvocate.org/news
/newsLetter/2004/advocate0604.html#1
July 28th, 2004
Idun Pharmaceuticals Initiates Phase 2 Clinical Study of IDN-6556 in Hepatitis C Virus
http://www.hcvadvocate.org/news/newsRev
/2004/NewsRev-59.html#4
Attacking the Hepatitis C Virus with New Mechanisms of Action: Drugs in the Pipeline
Paul J Pockros, M.D.
http://www.hcvadvocate.org/hcsp/articles
/Pockros-4.html
ISIS 14803
Chronological Listing of News Reviews and Releases:
Abstract Reports from the American Association for the Study of Liver Disease (AASLD 2002)
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Treatment of Chronic Hepatitis C with ISIS 14803, An Antisense Onligonucleotide Inhibitor of HCV. Effect of Target Region Sequence of Antiviral Effecacy—abstract 469
Muriel Soler, Hopital Henri Mondor, Universite Paris XII, Créteil, France; John G McHutchison, Scripps Clinic, La Jolla, CA; Jesse Kwoh, Andrew Dorr, Isis Pharmaceuticals, Carlsbad, CA; Jean-Michel Pawlotsky, Hopital Henri Mondor, Universite Paris XII, Créteil, France
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A Phase IB Dose Escalation Trial of ISIS 14803, an Antisense Inhibitor of HCV, in Patients with Chronic HCV: Final Report – abstract 562
J G McHutchison Sr., P J Pockros, K Patel, L Nyberg, Scripps Clinic, La Jolla, CA; R Z Yu, T J Kwoh, F A Dorr, Isis Pharmaceuticals, Inc., Carlsbad, CA
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A Phase II, 12-Week Study of ISIS 14803, an Antisense Inhibitor of HCV for the Treatment of Chronic Hepatitis C – abstract 795
On March 21 st, 2002 it was announced that HepaSense has Initiated a Phase II Clinical Trial of ISIS 14803 for Hepatitis C
http://www.hcvadvocate.org/news
/NewsUpdates_pdf/2.1.1.1_News%20Review
_Archive_2002 /NewsRev-4.pdf
November 5th, 2002
New Phase II Data Confirm ISIS 14803 Produces Significant Viral Level Reductions in Patients With Drug-Resistant Hepatitis C. Clinical Investigators Report Data From Two Clinical Trials
http://www.hcvadvocate.org/news
/NewsUpdates_pdf /2.1.1.1_News%20Review
_Archive _2002/NewsRev-11.pdf
February 2003 HCV Advocate
What Did We Learn From AASLD? Part 3
http://www.hcvadvocate.org/news/newsLetter
/advocate0203.html#3
June 09, 2003
Phase II Trial Launched to Test Possible HCV Therapy
John C. Martin, hepatitisneighborhood.com
http://www.hcvadvocate.org/news/newsRev
/NewsRev-18.html#44
Week Ending: June 12th, 2004
HCV ADVOCATE WEEKLY NEWS REVIEW: A Review of HCV, HBV and HIV/HCV Coinfection Related News and Highlights
Isis Pharmaceuticals (ISIS) Gains Full Ownership Of Orasense(TM) And HepaSense(TM) Subsidiaries And Eliminates Future Royalty Payments To Elan Corporation PLC (ELN)
http://www.hcvadvocate.org/news/newsRev
/2004/NewsRev-52.html#5
January 10th, 2005
Isis Pharmaceuticals to Slash Work Force
Isis said it will halt development of its ISIS 14803 drug for hepatitis C and ISIS 104838 treatment for rheumatoid arthritis.
http://www.hcvadvocate.org/news/newsRev
/2005/NewsRev-83.html#3
JTK-003
Source: http://www.hcvadvocate.org/hcsp
/articles/Pockros-4.html
Attacking the Hepatitis C Virus with New Mechanisms of Action: Drugs in the Pipeline
Paul J Pockros, M.D
HCV polymerase inhibitors
Based on the fundamental knowledge of the action of HCV enzymes during viral replication, a number of viral enzyme inhibitors are being developed. The HCV RNA polymerase inhibitors are to be the first enzyme inhibitors that were tested in patients. Phase I safety trials have been completed with a number of compounds. One of these (JTK-003, AkrosPharma, Inc.) has been studied in a randomised, doubleblind, placebo-controlled, ascending dose, multi-centre trial of patients with HCV. Data from this trial have not been made publicly available at this time. Although a helicase inhibitor has been in development, it has not yet been placed in human trials.
NM283
May 18, 2004
Idenix Pharmaceuticals, Inc. Announces First Human Clinical Trial Data For NM283 for the Treatment of Hepatitis C
Source: PRNewsire
Phase I/II clinical trial data presented at Digestive Disease Week (DDW)
NEW ORLEANS ,-- Idenix Pharmaceuticals, Inc. announced today the results of the first human clinical trial of NM283, a novel once-daily oral treatment for hepatitis C. In a Phase I/II dose escalation clinical trial, NM283, Idenix's first candidate for the treatment of hepatitis C, demonstrated consistent, dose-related antiviral effects in adult patients with chronic hepatitis C. The patient cohort that received the highest overall dose exposure of NM283 achieved a mean viral load reduction of 92 percent (1.1 log10) within 15 days of treatment. All patients were infected with HCV genotype 1, a difficult to treat strain, which is the predominant strain in the U.S. , Western Europe and Japan . Among the NM283-treated patients in the clinical trial to date, 87 percent had previously failed interferon-based therapies. The overall safety profile for NM283 in the Phase I/II trial was satisfactory, with no dose-limiting toxicities. These data were presented by Dr. Eliot Godofsky, the lead investigator in the study, at the Digestive Disease Week conference in New Orleans .
Study description: The double blind, randomized Phase I/II dose escalation clinical trial was designed to evaluate the safety, pharmacokinetics and antiviral activity of NM283 during 15 days of treatment with a two-week follow up period. All patients were chronically infected with the genotype 1 strain of HCV and were either previously untreated or had failed interferon-based therapy. Entry criteria for patients included serum HCV RNA levels greater than 5 log10 (100,000 international units (IU) per mL), ALT (a measure of liver disease) levels less than five times the upper limit of the normal range, and compensated liver disease without cirrhosis.
The design of the Phase I/II clinical trial included five once-daily dosing cohorts: 50, 100, 200, 400 and 800 mg and one twice-daily dosing cohort of 200 mg. Two further cohorts explored methods for optimizing tolerance of higher daily doses: one cohort initially received NM283 at 100 mg/day, advancing progressively to 800 mg/day for the second week of the clinical trial; the second cohort initially received NM283 at 400 mg/day, advancing progressively to 800 mg/day for the second week of the clinical trial, with anti-emetic treatment given together with NM283 for the first two days and for one day in conjunction with each of the two dose escalations. Each cohort included 12 patients, randomized so that 10 patients received NM283 and two received placebo. The once-daily 800 mg cohort is currently ongoing.
To date, a total of 82 patients comprising seven dose groups have completed treatment including 68 patients receiving assigned doses of NM283 and 14 receiving placebo. Patients enrolled in this clinical trial had a high baseline serum viral load (HCV RNA) with an average of 6.7 log10 IU/mL and the average serum ALT level at baseline was moderately elevated at 64 IU/L, reflecting underlying liver inflammation typical of hepatitis patients. The average age of the enrolled patients was 50 years (age range: 39 to 65 years).
Six clinical centers in the United States participated in the trial, including three university-based trial centers and three community-based trial centers. The trial was conducted under a U.S. FDA Investigational New Drug (IND) Application.
Study results: Consistent, dose-related reductions in serum HCV RNA were observed in patients receiving NM283. The greatest antiviral effect, with a mean HCV RNA reduction of 1.1 log10 IU/mL (92 percent), was experienced by patients who received the highest cumulative dose of NM283 over the 15-day treatment period. In this dosing group, 10 out of 10 patients demonstrated a significant reduction in HCV RNA ranging from 0.7 to 1.9 log10 IU/mL, corresponding to 79 to 99 percent viral load reductions. In this group, nine of the 10 patients had previously failed to respond to interferon-based therapies. For the three highest-dose groups in the clinical trial, antiviral responses over the 15-day treatment period exceeded the average serum viral level reduction of 0.3 log10 IU/mL per week observed in hepatitis C patients who respond to treatment with the current standard of therapy, ribavirin in combination with pegylated interferon.
The overall clinical safety profile seen in this trial has been good with no serious or treatment-limiting side effects. All 82 compliant patients completed treatment and follow-up; one patient was discontinued from the study for non-compliance. At the higher doses, some patients had mild-moderate gastrointestinal side effects that most often appeared in the first two days of treatment and typically resolved quickly. No patients changed or discontinued treatment due to any side effects.
Pharmacokinetics data revealed that NM283 was well absorbed by patients on treatment. There was no significant drug accumulation as Day 15 drug levels were comparable to Day 1 levels. Observed drug levels were proportional to the dose.
About NM283: NM283 is a novel antiviral drug that, after absorption, is metabolized to a form that inhibits the HCV RNA polymerase. NM283 has been shown to have synergistic antiviral effects with interferon-alpha in vitro. NM283 also inhibited HCV genotype 1 replication in chronically infected chimpanzees.
The next clinical trial will evaluate the combination of NM283 and pegylated interferon over a four-week treatment period. Longer-term trials of NM283 will follow in the second half of 2004.
About hepatitis C: There are approximately 170 million people worldwide with chronic hepatitis C virus (HCV) infection, of which approximately 2.7 million are in the United States . Chronic HCV infection accounts for 40 percent of end-stage cirrhosis, 60 percent of liver cancer and 30 percent of liver transplants in the United States and other industrialized countries. Available treatment options have tolerance issues and are often limited in their effectiveness; particularly in patients infected with HCV genotype 1, a specific strain of HCV that is the most treatment-resistant HCV genotype and that causes more than 70 percent of the reported cases of hepatitis C in the U.S. , Western Europe and Japan .
About Idenix: Idenix Pharmaceuticals, Inc. is a biopharmaceutical company engaged in the discovery and development of drugs for the treatment of human viral and other infectious diseases. Idenix's current focus is on the treatment of infections caused by hepatitis B virus, hepatitis C virus and human immunodeficiency virus (HIV). Idenix headquarters are located in Cambridge , Mass. and has drug discovery operations in Montpellier , France and Cagliari , Italy .
About DDW: Digestive Disease Week (DDW) is the largest international gathering of physicians, researchers and academics in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal surgery. Jointly sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA), the American Society for Gastrointestinal Endoscopy (ASGE) and the Society for Surgery of the Alimentary Tract (SSAT), DDW takes place May 15-20, 2004 in New Orleans , Lousiana. The meeting showcases approximately 5,000 abstracts and hundreds of lectures on the latest advances in GI research, medicine and technology.
CONTACT: Teri Babine, Idenix Public Relations, Idenix Pharmaceuticals, Inc., +1-617-995-9905; or Catherine London, Ruder Finn, Inc., Media Relations, +1-212-593-6309, for Idenix Pharmaceuticals, Inc. /
SOURCE Idenix Pharmaceuticals, Inc.
R803
Chronological Listing of Press Releases:
Rigel Pharmaceuticals, Inc.'s (RIGL) R803 for HCV Achieves Favorable Safety Profile
http://www.hcvadvocate.org/news/newsRev
/2004/NewsRev-33.html#5
Rigel Initiates Phase I/II Trial of R803 For The Treatment Of Hepatitis C Virus
http://www.hcvadvocate.org/news/newsRev
/2004/NewsRev-50.html#1
Rigel Hepatitis Drug Gets Poor Result
http://www.hcvadvocate.org/news/newsRev
/2004/NewsRev-76.html#3
Rituximab
Chronological Listing of News Reviews and Releases:
October 9th, 2004
Rituxan May Be Associated with HBV Reactivation and Fulminant Hepatitis
http://www.hcvadvocate.org/news/newsRev
/2004/NewsRev-69.html#8
Viramidine
November 01, 2002
Phase I Clinical Studies of Viramidine-A Liver-Targeting Prodrug of Ribavirin
Although ribavirin in combination with interferon has proven reasonably effective in the treatment of chronic HCV, use of the drug is limited by its many toxicities and side effects. Viramidine is a liver-targeting prodrug of ribavirin. It is efficiently converted to ribavirin by adenosine deaminases and effects similar direct and indirect anti-viral activities as ribavirin.
Pharmacokinetic (PK) studies in monkeys demonstrated that Viramidine is orally absorbed and preferentially taken up by the liver where the majority of the prodrug is converted to ribavirin. Animal toxicology studies resulted in no clinical side effects and minimal drop in hemoglobin in monkeys dosed at viramidine 600 mg/kg/day for 28 days while greater proportion of animals dosed at ribavirin 300 mg/kg/day experienced greater decrease in hemoglobin.
The aim of the current study was to characterize the safety and PK profiles of single dosing, the effect of food, and multiple dosing of viramidine in humans.
A rising-single dose (RSD) study to evaluate the safety, tolerability and PK profiles of viramidine at oral doses of 200, 600 and 1200 mg in male adult healthy volunteers (N=8 on viramidine vs. 2 on placebo per dose group) was conducted.
For the effect of food (FE), 36 adult male subjects were enrolled into 2 groups. Eighteen received viramidine 600 mg after 10-hr fasting and 18 received viramidine after a modified high fat breakfast. Subjects were crossed over to receive viramidine in reverse fasting/fed condition after a 6-wk washout.
A rising multiple-dose (RMD) study to determine the safety, PK and pharmacodynamics of viramidine at 400 mg BID, 600 mg BID and 800 mg BID for 4 weeks has been initiated in patients with chronic hepatitis C.
RSD and FE study - 57 healthy adult male subjects at mean age of 27.5 years (19-53 yrs) and mean weight of 76.4 kg (51-100 kg) completed the study. All doses of viramidine were safe and well tolerated.
All but one Hepseraerse events (AEs) were mild and comparable between the different dose levels of viramidine. Viramidine was orally absorbed and efficiently converted to ribavirin with Cmax for both compounds at Tmax of 2.5-3 hrs. Higher AUCs for viramidine-derived ribavirin compared to that of viramidine, by 2-3 folds, at all dose levels were observed.
Both Cmax and AUCs of viramidine-derived ribavirin were proportionally higher with increasing dose. Viramidine was not detectable in RBCs. AUC of viramidine-derived ribavirin in RBCs was about half of that compared to ribavirin dosing (historical data). Both viramidine and ribavirin were excreted in urine.
Mean AUC and Cmax of viramidine-derived ribavirin were 20% and 40% higher, respectively, after fed than fasting. RMD study is in progress with results available for presentation at AASLD.
Conclusions:
Single doses of viramidine up to 1200 mg are safe and well tolerated in humans.
Viramidine is orally absorbed and efficiently converted into ribavirin.
The linear relationship between Cmax and AUC of viramidine-derived ribavirin with viramidine dose indicates dose proportionality.
The exposure of viramidine-derived ribavirin to RBC is about half that after ribavirin dosing suggesting a lesser potential in inducing hemolytic anemia than ribavirin.
The marginal effects of food are not likely to be clinically relevant when the treatment duration is as long as 48 weeks.
January 22, 2003
Viramidine to Advance to Phase II Clinical Trials in Hepatitis C Phase I Clinical Trial Data Presented at the 53rd Annual Meeting of the American Association for the Study of Liver Diseases
Ribapharm Inc., today announced it will commence phase II clinical trials of viramidine in the treatment of chronic hepatitis C (HCV) by the end of 2002. Data from several preclinical and phase I clinical studies on viramidine were presented at the ongoing 53 rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in Boston, MA.
Viramidine is a nucleoside analogue structurally related to ribavirin. Ribavirin is currently approved in the combination treatment with interferon alpha or pegylated interferon alpha in patients with clinically
compensated chronic hepatitis C infection. Ribapharm filed an Investigational New Drug application ( IND ) for viramidine with the U.S. Food and Drug Administration (FDA) in December 2001.
“Biochemical and animal studies showed that viramidine is converted to ribavirin predominately in the liver, the organ infected by hepatitis C,” said Jane W.S. Fang, MD, Vice President of Clinical Affairs and Clinical
Operations at Ribapharm. “Given the results from the phase I studies, we anticipate initiating phase II studies on the combination use of viramidine and pegylated interferon alpha before the end of 2002.”
“A phase I rising multiple-dose study with viramidine dosing from 800 mg per day to 1,600 mg per day for four weeks was conducted. There was no significant decrease in hemoglobin levels even with the highest
doses (1,600 mg per day) of viramidine,” said Daryl Lau, MD, Assistant Professor of Medicine, University of Texas Medical Branch in Galveston and a study investigator.
Preclinical studies of viramidine were also presented at the AASLD meeting. Studies in monkeys showed that 28 days of viramidine dosing up to 600 mg/kg per day induced no significant change in hemoglobin
levels in males and a mild decrease of less than 10% from baseline in females. In the same study, ribavirin at 300 mg/kg per day induced a decrease of hemoglobin of 11-14% in male and 23-25% in female monkeys.
“Preclinical studies provided scientific support for viramidine to proceed to advanced clinical studies,” said
Chin-chung Lin, PhD, Vice President, Drug Development at Ribapharm.
About Hepatitis C
Hepatitis C is an inflammatory liver disease, caused by the infection of the hepatitis C virus. Globally, an estimated 170 million persons are chronically infected with hepatitis C and three to four million are newly
infected each year. HCV is now four times as widespread as HIV in the U.S.
In June 2002, the National Institutes of Health (NIH) convened a Consensus Conference Panel to examine current management and treatment practices for hepatitis C. The panel noted that the hepatitis C virus is the leading cause of chronic liver diseases in the United States , including liver cirrhosis and hepatocellular carcinoma. In a final consensus statement, the NIH panel concluded that the most effective treatment of chronic hepatitis C is with a combination therapy of pegylated interferon alpha and ribavirin.
About Ribapharm
Ribapharm is a biopharmaceutical company that seeks to discover, develop, acquire and commercialize innovative products for the treatment of significant unmet medical needs, principally in the antiviral and anticancer areas.
May 18, 2004
Valeant Pharmaceuticals Presents Details of Viramidine 24-Week Data From Phase 2 Trials
Source: PRNewswire
COSTA MESA, Calif.,-- Valeant Pharmaceuticals (NYSE: VRX) today presented detailed 24-week data from Phase 2 clinical trials of Viramidine, a nucleoside (guanosine) analog Valeant is developing in oral form for the treatment of chronic hepatitis C (HCV) in conjunction with a pegylated interferon. Valeant presented its data at the Digestive Disease Week (DDW) Conference in New Orleans . This presentation complements data presented at the European Association for the Study of the Liver (EASL) in April 2004.
The Viramidine Phase 2 study consists of 180 treatment-naive subjects with chronic HCV. The on-going study was an open-label, randomized, active control trial, being conducted at multiple centers in the United States and with patients stratified by genotype. The study consists of four demographically comparable treatment groups: Viramidine 400 mg BID, Viramidine 600 mg BID, Viramidine 800 mg BID and ribavirin 1000/1200 mg daily all in combination with peginterferon alfa-2a. Treatment duration was based on genotype, with genotypes two and three receiving 24 weeks of treatment and genotype one receiving 48 weeks of treatment, each with a post-treatment follow-up period of 24 weeks.
The data demonstrate that a smaller portion of patients who received Viramidine 800-1200 mg/day had hemoglobin levels 10 g/dL or greater than or equal to 2.5 g/dL drop from baseline during the 24-week treatment period when compared to patients who had received ribavirin (48 percent versus 82 percent, respectively).
Among patients who received Viramidine 800-1200 mg/day, there were no instances of hemoglobin 10g/dL in either male or female patients. In the ribavirin group, 19 percent of male patients and 38 percent of female patients experienced hemoglobin levels 10g/dL. Differences between genders were not observed in the occurrence of a greater than or equal to 2.5 g/dL decrease in hemoglobin.
Data addressing effects on hemoglobin levels were also presented at DDW. After 12 weeks of treatment, the mean RBC ribavirin C(min) was 159 (mu)g/mL in patients who received Viramidine 1200 mg/day compared to 235 (mu)g/mL in ribavirin-treated patients. Thirteen percent of ribavirin-treated patients experienced declines in hemoglobin, requiring dose reduction or discontinuation, versus zero percent for the Viramidine group. These differences were reflected in the clinical outcomes at week 24, where a smaller proportion of patients who received Viramidine 800-1200 mg/day had hemoglobin 10 g/dL (zero percent versus 24 percent) or greater than or equal to 2.5 g/dL decrease from baseline (48 percent versus 82 percent) when compared with ribavirin-treated patients.
Data were presented by Robert Gish, M.D., the lead investigator on the Viramidine Phase 2 study and Medical Director of the Liver Transplant Program at California Pacific Medical Center in San Francisco and Sanjeev Arora, M.D., Professor of Gastroenterology and Internal Medicine Vice Chairman of Clinical Affairs for the Department of Medicine at the University of New Mexico .
A Phase 3 clinical trial, called VISER1, comparing Viramidine to ribavirin in combination with Peg-Intron was initiated in the fourth quarter of 2003 and is ongoing.
The Phase 3 trial compares the 600 mg BID dose of Viramidine to ribavirin, each in conjunction with pegylated interferon alpha 2b.
Data presented at EASL earlier this year demonstrate a sustained reduction in HCV RNA of approximately two-and-a-half log(10) for all three doses of Viramidine, comparable to the ribavirin group in the same study. The proportion of patients with greater than or equal to 2 log(10) reduction or non-detectable HCV RNA was 83 percent for both Viramidine (800-1600 mg/day) and ribavirin at 24 weeks. The results also show the percent of patients with non-detectable HCV RNA at 12 weeks and 24 weeks were similar between all treatment groups.
There were also fewer patients in the Viramidine groups with anemia (defined as hemoglobin 10g/dL) when compared with the ribavirin arm (2 percent versus 24 percent; p 0.001). In the Viramidine 400 mg BID and 600 mg BID dosage groups, defined anemia (hemoglobin 10g/dL) did not occur, while there were only two occurrences of anemia in the 800 mg BID group. Other adverse events were similar among treatment groups.
About Valeant Valeant Pharmaceuticals International (NYSE: VRX) is a global, publicly traded, research-based specialty pharmaceutical company that discovers, develops, manufactures and markets a broad range of pharmaceutical products. More information about Valeant can be found at www.valeant.com.
FORWARD-LOOKING STATEMENTS This press release contains forward-looking statements within the meaning of the federal securities laws relating to expectations, plans or prospects for Valeant Pharmaceuticals, including funding and conducting clinical trials and expected research and development expenses. These statements are based upon the current expectations and beliefs of Valeant Pharmaceuticals' management and are subject to certain risks and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements. These risks and uncertainties include market conditions and other factors beyond Valeant Pharmaceuticals' control, the company's success in identifying and enrolling patients in the clinical trials program, the absence of adverse events that would require the clinical trials to be prematurely terminated, clinical results that indicate continuing clinical and commercial pursuit of Viramidine is advisable, and the risk factors and other cautionary statements discussed in Valeant Pharmaceuticals' filings with the U.S. Securities and Exchange Commission.
October 01, 2004
Valeant Pharmaceuticals to Present Viramidine(TM) End-of-Treatment Data From Phase 2 Clinical Trial
Source: PRNewswire
COSTA MESA, Calif.,-- Valeant Pharmaceuticals (NYSE:VRX) announced that an abstract based on Viramidine(TM) 48-week end-of-treatment study data will be posted to the American Association for the Study of the Liver Conference (AASLD) Web site. Valeant submitted the abstract for presentation at AASLD based on data from a Phase 2 clinical trial of Viramidine, a nucleoside (guanosine) analog Valeant is developing in oral form for the treatment of chronic hepatitis C (HCV) in conjunction with a pegylated interferon. Valeant will present the data at AASLD in Boston in October 2004.
The Viramidine Phase 2 study consists of 180 treatment-naive subjects with chronic HCV. The on-going study is an open-label, randomized, active control trial, being conducted at multiple centers in the United States and with patients stratified by genotype. The study consists of four demographically comparable treatment groups: Viramidine 400 mg BID (800 mg daily), Viramidine 600 mg BID (1200 mg daily), Viramidine 800 mg BID (1600 mg daily) and ribavirin 1000/1200 mg daily all in combination with peginterferon alfa-2a. Treatment duration was based on genotype, with genotypes two and three receiving 24 weeks of treatment and genotype one receiving 48 weeks of treatment, each with a post-treatment follow-up period of 24 weeks. The 24-week follow-up period is considered the medically therapeutic standard evaluation of efficacy.
The end-of-treatment analysis was conducted to determine the incidence of anemia (hemoglobin<10g/dL) and also assessed HCV RNA levels (Bayer TMA assay; sensitivity to 5 IU/mL, 25 copies/mL).
At end of treatment, fewer patients developed anemia in the Viramidine arms than in the ribavirin arm (4 percent versus 27 percent; p<0.001). Among patients receiving the 400 mg BID dosage of Viramidine, there were no cases of defined anemia and among patients receiving the 600 mg BID dosage there was only one case of defined anemia (2 percent). In contrast, there was an 11 percent incidence of defined anemia in the 800 mg BID arm and a 27 percent incidence in the ribavirin arm. Other types of adverse events were similar between treatment arms. (The most common adverse events associated with combination therapy are fatigue, headache, insomnia, depression and myalgia.) Differences noted in efficacy were not statistically significant between the Viramidine arms versus ribavirin (Viramidine 400 mg BID - 55 percent, 600 mg BID - 63 percent, 800 mg BID - 56 percent, versus ribavirin - 62 percent; p=NS), all in combination with pegylated interferon alfa-2a, in the proportion of patients with undetectable HCV RNA levels.
Two Phase 3 clinical trials of Viramidine 600mg BID, known as VISER1 and VISER2 (VIramidine's Safety and Efficacy vs. Ribavirin), are being conducted with approximately 100 sites and approximately 1,000 patients in each study. VISER1 compares Viramidine to ribavirin, in combination with Schering-Plough's Peg-Intron(R), and completed enrollment in July. VISER2 compares Viramidine to ribavirin, in combination with Roche's Pegasys(R), and is currently enrolling patients. Phase 3 is the last phase in a multi-phase clinical evaluation that may lead to the filing of a New Drug Application.
About Valeant
Valeant Pharmaceuticals International (NYSE:VRX) is a global, publicly traded, research-based specialty pharmaceutical company that discovers, develops, manufactures and markets a broad range of pharmaceutical products. More information about Valeant can be found at www.valeant.com.
FORWARD-LOOKING STATEMENTS
This press release contains forward-looking statements within the meaning of the federal securities laws relating to expectations, plans or prospects for Valeant Pharmaceuticals, including funding and conducting clinical trials and expected research and development expenses. These statements are based upon the current expectations and beliefs of Valeant Pharmaceuticals' management and are subject to certain risks and uncertainties that could cause actual results to differ materially from those described in the forward- looking statements. These risks and uncertainties include market conditions and other factors beyond Valeant Pharmaceuticals' control, the company's success in identifying and enrolling patients in the clinical trials program, the absence of adverse events that would require the clinical trials to be prematurely terminated, clinical results that indicate continuing clinical and commercial pursuit of Viramidine is advisable, and the risk factors and other cautionary statements discussed in Valeant Pharmaceuticals' filings with the U.S. Securities and Exchange Commission.
For further information please contact: Jeff Misakian of Valeant Pharmaceuticals, +1-714-545-0100 ext. 3309
Source: Valeant Pharmaceuticals
CONTACT: Jeff Misakian of Valeant Pharmaceuticals,
+1-714-545-0100 ext. 3309
VX-950
From AASLD 2003 Conference Coverage -
Poster 972: VX-950: THE DISCOVERY OF AN INHIBITOR OF THE HEPATITIS C NS3•4A PROTEASE AND A POTENTIAL HEPTITIS C VIRUS THERAPEUTIC
Robert B Perni, Gurudatt Chandorkar, Pravin R Chaturvedi, Lawrence F Courtney, Caroline J Decker, Cynthia A Gates, Scott L Harbeson, Ann D Kwong, Chao Lin, Yu-Ping Luong, William Markland, Govinda Rao, Roger D Tung, John A Thomson, Vertex Pharmaceuticals Inc., Cambridge, MA
INTRODUCTION
The deficiencies of current anti-HCV therapy are well known. The poor tolerability of the interferon-alpha (IFN-alpha)-ribavirin combination therapy limits its value, particularly versus Genotype 1 where even the pegylated IFN-alpha/ribavirin combinations are generally less than 50% effective in achieving sustained viral responses. The need for a direct anti-viral therapy for hepatitis C is clear. The NS3•4A protease of the hepatitis C virus represents an attractive target that should be amenable to modern drug design techniques. Designing small molecules that have high affinity for the shallow, largely hydrophobic active site of this serine protease has been a significant challenge and only recently the first HCV protease inhibitor to show anti-viral activity in humans was reported (Lamarre et al, 2002, Hepatology, 36, Pt2, 301A). Nature has designed this protein with a natural substrate recognition sequence of a lengthy 10 amino acids. Consequently, numerous hydrophobic interactions and hydrogen bonds are required to effectively bind any potential inhibitor. In addition, either a charged terminus or a covalent attachment of the inhibitor to the catalytic serine is needed to anchor the assembly. To maximize binding while simultaneously maintaining an acceptable biological profile, we have chosen to base our inhibitor scaffolds on a reversible covalent warhead motif in order to eliminate charged groups and facilitate cellular penetration. We now report the discovery of VX-950, a small molecule inhibitor of the hepatitis C NS3•4A protease. This molecule was derived through structure-based drug design methodology, evolving from the natural NS5A-NS5B substrate. VX-950 has a measured Ki of 44 nM versus the NS3•4A enzyme. Inhibition of the polyprotein processing in hepatocytes as measured by the HCV replicon assay has been demonstrated. VX-950 is orally bioavailable in several species with a favorable pharmacokinetic profile. The uptake of the drug is characterized by first pass hepatic extraction resulting in high concentrations of drug in the liver, which should be advantageous for treatment of chronic HCV. On the basis of these attributes VX-950 has been selected for clinical evaluation in humans.
Conclusion
-
HCVNS3-4A protease inhibitor VX 950 has been identified as a development candidate for the treatment of HCV
-
VX 950 has demonstrated good cellular activity in two assays. The anti viral activity can be sustained in viral clearance assays resulting in a continuing decline of HCV RNA for 9 days
-
This is possibly a function of the slow binding enzyme mechanism
-
Higher liver exposures have been achieved
-
This reversible tight slow binding was discovered suing structure based drug design
-
Clinical trials are planned to begin in early 2004
The authors wish to gratefully acknowledge the significant contributions to this research by our collaborators at Eli Lilly and Co
September 7th, 2004
Vertex Pharmaceuticals Reports Completion of Dosing in the Phase 1a Clinical Study of VX-950, an Oral HCV Protease Inhibitor for the Treatment of Hepatitis C
Source: PRNewswire
CAMBRIDGE, Mass.-- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced it has successfully completed the dosing portion of a Phase Ia clinical trial for VX-950, an investigational oral protease inhibitor for the treatment of hepatitis C virus (HCV) infection. The study, involving 35 healthy volunteers and conducted in Europe, was designed to assess safety, tolerability and pharmacokinetics in escalating, single doses of VX-950. Based on the results from this study and preclinical studies, the Company expects to begin a Phase 1b clinical study of VX-950 in HCV-infected patients by the end of the year.
"As an oral, direct antiviral therapy, VX-950 represents an exciting novel approach for the treatment of chronic hepatitis C infection," stated John J. Alam, M.D., Senior Vice President of Drug Evaluation and Approval at Vertex. "VX-950 is a key compound in our core HCV drug development portfolio, and the completion of the Phase I study represents another important step forward for this clinical development program."
In the Phase Ia study, single doses ranging from 25 mg to 1250 mg were administered. No dose-limiting toxicities were identified, and a maximum tolerated dose was not reached. However, blood concentrations of VX-950 were observed that exceeded the concentration known to demonstrate potent antiviral activity in preclinical laboratory experiments, and at certain dose levels these target concentrations were maintained for more than 12 hours. Analysis of combined clinical and preclinical pharmacokinetic results for VX-950 suggest that liver concentrations 10- to 30-fold above the replicon 50% inhibitory concentration ("IC50") are achievable in humans using practical doses and regimens. The liver is the target organ for antiviral therapies directed against hepatitis C infection.
"The data from the Phase I study met our expectations, and we look forward to the first evaluation of VX-950 in HCV-infected patients," stated Dr. Alam. "While extrapolations based on single dose studies must be made with caution, the concentrations of VX-950 we observed in the bloodstream of healthy volunteers are at levels which we would expect to be required to demonstrate antiviral activity when VX-950 is dosed in HCV-infected patients."
In the fourth quarter of 2004, Vertex expects to initiate a multi-dose, Phase Ib clinical study with VX-950. This placebo-controlled trial will be designed to evaluate the safety, tolerability, and pharmacokinetics of up to 14 days of dosing with VX-950 in both healthy volunteers and HCV-infected patients. The data from the Phase Ia study, together with data from nonclinical studies, are being compiled for submission to the appropriate regulatory authorities for review prior to initiation of the Phase Ib study.
About VX-950 and Hepatitis C
VX-950 is Vertex's lead oral HCV protease inhibitor and one of the most advanced of a new class of antivirals in development for HCV. Preclinical data have shown that VX-950 significantly reduces levels of HCV-RNA in both the replicon system and infectious virus assays within days. Preclinical pharmacokinetic studies completed to date have indicated that VX-950 is orally bioavailable and achieves excellent exposure in the liver, the target organ for HCV treatment.
Chronic hepatitis C virus infection is a serious public health concern affecting approximately 2.7 million people in the United States. HCV causes inflammation of the liver, which may lead to fibrosis and cirrhosis, liver cancer, and ultimately, liver failure. Cirrhosis of the liver resulting from chronic HCV infection is the leading indication for liver transplantation in the U.S. Due to the asymptomatic nature of HCV infection, it often goes undetected for up to 20 years following initial infection. Worldwide, the disease strikes as many as 185 million people. Each year, 8,000 to 10,000 people in the U.S. die from complications of HCV.
Collaboration with Mitsubishi Pharma Corporation
In June 2004, Vertex and Mitsubishi Pharma Corporation signed an agreement to develop and commercialize VX-950 in Japan and certain Far East countries. Mitsubishi will make pre-commercial payments to Vertex to support clinical development of VX-950. Additionally, Mitsubishi will pay royalties to Vertex on commercial sales of VX-950 in Mitsubishi's territories. Vertex owns development and commercialization rights to VX-950 in the rest of the world, including North America and Europe.
About Vertex
Vertex Pharmaceuticals Incorporated is a global biotechnology company committed to the discovery and development of breakthrough small molecule drugs for serious diseases. The Company's strategy is to commercialize its products both independently and in collaboration with major pharmaceutical partners. Vertex's product pipeline is principally focused on viral diseases, inflammation, autoimmune diseases and cancer. Vertex co-promotes the new HIV protease inhibitor, Lexiva(R), with GlaxoSmithKline.
This press release may contain forward-looking statements, including statements that (i) preclinical and Phase I clinical results support the initiation of a Phase Ib clinical study in HCV-infected patients; (ii) a Phase Ib study is planned for the fourth quarter of 2004; and (iii) the concentrations of VX-950 observed in the bloodstream of healthy volunteers suggest that antiviral activity will be observed in HCV-infected patients. While management makes its best efforts to be accurate in making forward-looking statements, such statements are subject to risks and uncertainties that could cause Vertex's actual results to vary materially. These risks and uncertainties include, among other things, the risks that clinical trials for VX-950 may not proceed as planned due to technical, scientific, supply or patient enrollment issues, that subsequent clinical studies of VX-950 will not reflect the results obtained in nonclinical and initial clinical testing, that clinical results may not demonstrate the value of VX-950, and other risks listed under Risk Factors in Vertex's form 10-K filed with the Securities and Exchange Commission on March 15, 2004.
Lexiva(R) is a registered trademark of the GlaxoSmithKline group of companies. Vertex's press releases are available at http://www.vrtx.com.
Vertex Contacts:
• Lynne Brum, Vice President, Corporate Communications and Financial Planning, (617) 444-6614
• Michael Partridge, Director, Corporate Communications, (617) 444-6108
• Jaren Irene Madden, Manager, Media Relations, (617) 444-6750
From AASLD 2004
Presentation Time: 10/31/2004 12:30:00 PM Program#/Poster#: 552
IN VITRO RESISTANCE MUTATIONS AGAINST VX-950 AND BILN 2061, TWO HCV PROTEASE INHIBITOR CLINICAL CANDIDATES: SINGLE-RESISTANCE, CROSS-RESISTANCE, AND FITNESS
Chao Lin, B. Govinda Rao, Yu-Ping Luong, John R. Fulghum, Debra L. Brennan, Yun-Yi Wei, J. Daniel Frantz, Judith Lippke, Hsun-Mei Hsiao, Sue Ma, Kai Lin, John P. Maxwell, Kevin M. Cottrell, Cynthia A. Gates, Robert B. Perni, Ann D. Kwong, Vertex Pharmaceuticals Incorporated, Cambridge, MA.
Introduction:
VX-950, a small molecule inhibitor of the HCV NS3•4A protease, was optimized using a structure-based drug design approach. In this report, we describe in vitro resistance studies on VX-950 and another HCV protease inhibitor, BILN 2061, using a sub-genomic replicon system. The primary resistance mutation against VX-950 remains sensitive to BILN 2061, and the dominant BILN 2061-resistant mutations remain fully susceptible to VX-950.
Results:
Our structural analysis suggests that these dominant resistance mutations develop in response to VX-950 or BILN 2061 via different mechanisms. In addition, cross-resistance mutations were identified under selection with both HCV protease inhibitors. Steric hindrance appears to be the primary cause for loss of drug susceptibility for the primary VX-950-resistant mutation as well as the cross-resistance mutations. Fitness studies indicate that these resistance mutations are compromised in their ability to support HCV replication in the replicon system.
Conclusion:
-
A single amino acid substitution can be sufficient to confer in vitro resistance against HCV NS23-4A protease inhibitors
-
The dominant resistance mutations against BILN 2061, D168 are fully susceptible to VX-950
-
The dominant resistance mutation against VX-950, A156S, remains sensitive to BILN 2061
-
A156T and A156V are cross-resistant to both HCV NS3-4A protease inhibitors VX-950 and BILN 2061
From AASLD 2004
Program#/Poster#: LB-20
RESULTS OF A PHASE I SINGLE-DOSE ESCALATION STUDY OF THE HEPATITIS C PROTEASE INHIBITOR VX-950 IN HEALTHY VOLUNTEERS
Hui-May Chu, Lindsay McNair, Susan Purdy, Vertex Pharmaceuticals Inc., Cambridge, MA.
Introduction:
VX-950, a highly selective peptidomimetic inhibitor of the Hepatitis C virus (HCV) NS3•4A protease, is designed to block HCV replication and is being developed for the treatment of HCV infection.
Methods:
We have conducted a single-dose escalation, placebo-controlled study designed to evaluate the safety, tolerability, and pharmacokinetics of orally administered VX-950 in 25 healthy male volunteers. Doses of 25 mg to 1000 mg of VX-950 have been evaluated.
Results:
Clinical data demonstrated that VX-950 was well tolerated at these doses. There were no serious or severe adverse events reported. Most adverse events were mild, and were non-specific in nature, such as fatigue, headache, and nausea. There were no clinically significant laboratory abnormalities reported. A pharmacokinetic assessment showed that VX-950 was orally bioavailable. The relationship between VX-950 dose and exposure was more than proportional. The apparent elimination half-life of the drug ranged from 2 to 6 hours with a median of approximately 4 hours in the >450 mg dose range, and 1.5 to 3 hours with a median of approximately 2 hours in the 25 to 300 mg dose range. The exposure of the drug in the plasma exceeded 50% of the inhibitory concentration (IC50) (replicon IC50 = 240 ng/mL) for at least 10% of the time (at the 450 mg dose), and 100% of the time (at doses of 750 mg and 1000 mg), during a 12-hour period. Based on these data and extensive pre-clinical data on plasma-to-liver drug concentration ratios, the doses are also expected to yield liver exposures that exceed 90% of the inhibitory concentration (IC90) (replicon IC90 = 476 ng/mL) during a 12-hour period.
Conclusions:
This initial clinical study of VX-950 demonstrates acceptable safety, tolerability, and appropriate pharmacokinetics, supporting the continued development and exploration of VX-950 in subjects with HCV. A multiple dosing study in both a healthy volunteer and HCV-positive subject population is now being planned.
November 1st, 2004
Vertex Hepatitis Drug Dosing to Advance
Associated Press
Biotech company Vertex Pharmaceuticals Inc. reported Monday that it plans to begin enrolling the next phase of early stage clinical trials for its Hepatitis C drug this month after finding no initial safety concerns.
In a Phase Ia dose-escalation study, Vertex found that VX-950 was well-tolerated in healthy individual in doses ranging from 25 milligrams to 1250 milligrams. The company said there were no serious adverse events in the trial and that higher doses of the drug did not appear to increase adverse events.
The Phase Ib part of the trial will enroll healthy volunteers and patients with chronic hepatitis C virus infection. The trial will follow subject on 14-day dosing regimens of the drug.
VX-950 is among a class of antiviral drugs known as protease inhibitors and has been shown to reduce levels of Hepatitis C virus within days in preclinical testing, the company said.
Chronic Hepatitis C virus affects about 2.7 million people in the United States .
Shares of Vertex rose 41 cents, or 3.8 percent, to $11.29 in midday trading on the Nasdaq.
Merimepodib (MPB) (VX-497)
Chronological Listing of News Reviews and Releases:
May 2004 HCV Advocate EASL 2004 Update
Merimepodib
Merimepodib (MPB) (VX-497) is a selective inhibitor of IMPDH. In a study by P. Marcellin and colleagues, 31 patients with genotype 1 who were nonresponders to prior interferon and ribavirin therapy were enrolled. The participants were randomized to receive VX-497, 25 or 50 mg every twelve hours, or a placebo drug in combination with pegylated interferon plus ribavirin for 24 weeks. Trial participants with no detectable viral load at 24 weeks received treatment for an additional 24 weeks. All participants were then followed post-treatment to determine sustained virological response.
The report for the 24 weeks (preliminary results) found that the highest dose of VX-497 when com-bined with pegylated interferon plus ribavirin produced the highest number of patients with unde-tectable viral load—85%. The authors concluded that “the addition of VX-497 at a dose of 50 mg to pegylated interferon and ribavirin was well-tolerated and showed an enhanced anti-viral effect at 24 weeks in the interferon/ribavirin non-responder population.” The post-treatment follow-up SVR’s are eagerly awaited.
http://www.hcvadvocate.org/news
/newsLetter/2004/advocate0504.html
A Phase II, Placebo-Controlled Study of Merimepodib (VX-497), in Combination with Pegylated Interferon-Alfa, and Ribavirin in Patients with Chronic Hepatitis C Non-Responsive to Previous Therapy with Interferon-Alfa and Ribavirin
P. Marcellin 1 ,Y. Horsmans F 2 ,Nevens 3, J.D.Grange 4 ,J.P.,Bronowicki 5, D. Vetter 6 ,R. Kauffman 7 ,S. Knox L. McNair 7 ,S. Moseley 7 ,J. Alam 7
1 Service D ‘Hepatologie, Hopital Beaujon, Clichy, France; 23 Dept of Gastroentemlogy, UCL, Brussels, Belgium; 3 of Hepatology, KUL, Leuven, Belgium; 4 D ‘Hepatogastroentemlgie, Hopital Tenon, Paris, France; 5 D ‘Hepatogastroenterolgie, Vandoevre Les Nancy. Nancy, France; 6 D’Hepatogastroenterolgie, Hopital Civil, Strasbourg, France; 7 Phannaceuticals, Cambridge MA, USA
Introduction
Merimepodib (MPB) (VX-497) is a novel, selective inhibitor of inosine monophosphate dehydrogenase (IMPDH). In the HCV replicon system, MPB shows potent anti-viral effects. As monotherapy for 28 days MPH reduces serum transaminase levels, and in a 28-day dual combination modestly enhances the antiviral effect of interferon alfa in patients with chronic hepatitis C (CHC).
Aim
In this study we evaluated the addition of MPB to pegylated (Peg) IFN and ribavirin (RBV), in patients who were non- responders to IFN and RBV
Methods
Thirty-one patients with genotype 1 CHC who had not responded to prior IFN and RBV therapy were randomized to receive MPH, 25 or 50 mg q12h or placebo orally, in combination with Peg-IFN and RBV for 24 weeks. Patients with no detectable virus at 24 weeks received the same treatment for an additional 24 weeks then were followed post- treatment to ascertain sustained response.
Results
The three treatment groups were similar in baseline HCV-RNA and ALT. The combination of Peg-IFNIRBVIMPB was well tolerated.
-
Peg-IFN/RBV/Placebo, 3/10(30%);
-
Peg-IFN/RBV/IMPB 25 mg, 2/10(20%);
-
Peg-IFN/RBV/MPB 50 mg, 8/11(73%),
p=0.O2* .
p=O.3*
(*JonckheereTerpstra test for increasing dose response)
Conclusion:
The addition of MPB at a dose of 50 mg, to Peg-IFN and RBV was well tolerated and showed an enhanced anti-viral effect at 24 weeks in an IFN-RBV non-responder population.
http://www.hcvadvocate.org/news
/reports/EASL_2004/EASL_Misc.htm
Zadaxin
Chronological Listing of News Reviews and Releases:
HCV Advocate News Review #5
On May 22nd, 2002 SciClone Pharmaceutical released a press release titled “ZADAXIN(R) Selectively Stimulates Immune System-Related Genes Important In the Fight Against Hepatitis C - Study Presented at the AASLD's Digestive Disease Week”
HCV Advocate News Review #11
ZADAXIN Adds Benefit to Pegylated Interferon for HCV Non-Responders; Hepatitis C Patients Who Failed Prior Therapy Responding to ZADAXIN
http://www.hcvadvocate.org/news
/NewsUpdates_pdf /2.1.1.1_News%20Review_Archive_2002
/NewsRev-11.pdf
ZADAXIN Combination Therapy Shows 71% Sustained Response in Hepatitis B Patients
http://www.hcvadvocate.org/news
/newsRev/NewsRev-16.html#26
September 1st, 2003
Finding the Right Combination to Fight Hepatitis C
http://www.hcvadvocate.org/news
/newsRev/NewsRev-21.html#47
Check-up: Hepatitis C http://www.hcvadvocate.org
/news/newsRev/NewsRev-23.html#16
February 18th, 2004
SciClone Pharmaceuticals (SCLN) Reports Data: 41% Of Hepatitis C Non-Responder Patients Test HCV RNA Negative After 24 Weeks Of ZADAXIN Triple Therapy
http://www.hcvadvocate.org/news
/newsRev/2004/NewsRev-36.html#8
April 14, 2004
Explores New Combination Therapy In Hepatitis B Clinical Trial
Trial Uses High Dose of ZADAXIN in Combination with Lamivudine
http://www.hcvadvocate.org/news
/newsRev/2004/NewsRev-44.html#4
May 20, 2004
SciClone Achieves Enrollment Milestone For U.S. Phase 3 Hepatitis C Trials; Earns $1,000,000 Milestone Payment http://www.hcvadvocate.org/news
/newsRev/2004/NewsRev-49.html#10
November 1st, 2004
SciClone's ZADAXIN Shows Promise in Triple Therapy Trial for Hepatitis C Non-Responder Patients; Endpoint Data Presented at World's Largest Meeting of Liver Specialists American Association of the Study of Liver Disease (AASLD) http://www.hcvadvocate.org/news
/newsRev/2004/NewsRev-73.html#5
BILN 2061
Chronological Listing of News Reviews and Releases:
October 14th, 2003
Future Hepatitis C Treatments
http://www.hcvadvocate.org/news
/newsRev/NewsRev-23.html#37
December 2003 HCV Advocate
AASLD Conference Highlights: Part 2
http://www.hcvadvocate.org/news
/newsLetter/advocate1203.html#1
April 16th, 2004
Vertex Pharmaceuticals (VRTX) Reports Data on Investigational Hepatitis C Therapies Suggesting Potential For Novel Treatment Approaches
http://www.hcvadvocate.org/news
/newsRev/2004/NewsRev-44.html#10
HEPATITIS JOURNAL REVIEW:
December 31, 2004 Volume 1, Issue 20
Promising Results for BILN-2061, but Studies Put on Hold
“Further clinical trials of BILN-2061 have been put on hold “pending resolution of animal toxicity issues.” Although the agent was well tolerated in preclinical toxicology studies and short-term clinical trials to date, cardiac problems seen in monkeys given high doses of the drug for four weeks have raised concerns that the company seeks to address before proceeding with further trials in humans”
http://www.hcvadvocate.org/news
/newsRev/2004/HJR-1.20.html#4
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