Nov. 1, 2010, 8:00 a.m. EDT
TORONTO and NEW YORK, Nov. 1, 2010 /PRNewswire via COMTEX/ -- Valeant Pharmaceuticals International, Inc. /quotes/comstock/13*!vrx/quotes/nls/vrx (VRX 27.76, +0.15,
+0.54%) /quotes/comstock/11t!e:vrx (CA:VRX 28.22, 0.00, 0.00%) and Kadmon Pharmaceuticals LLC have concluded two strategic agreements for the development and commercialization of taribavirin and the commercial marketing of ribavirin in the treatment of viral diseases, including hepatitis C virus (HCV). Under the terms of the first agreement, Valeant grants Kadmon an exclusive, worldwide license to taribavirin, excluding the territory of Japan, in exchange for an upfront payment of $5 million, other development milestones, and royalty payments in the range of 8-12% of future net sales. Under a separate agreement, Valeant has paid Kadmon $7.5M for exclusive rights to all Kadmon dosage forms of ribavirin, including 200mg, 400mg, and 600mg tablets and capsules, in Poland, Hungary, Czech Republic, Slovakia, Romania and Bulgaria. Valeant will source these products from Kadmon.
J. Michael Pearson, CEO of Valeant Pharmaceuticals, said: "We are pleased to find a strong partner for a compound that we believe has potential to help patients in need of improved treatment. While participating in product development in the overall hepatitis C market no longer fits within our corporate development strategy, ribavirin should be a significant product for our branded generics portfolio in Central Europe."
Samuel D. Waksal, CEO of Kadmon Pharmaceuticals, said: "Kadmon is building upon its commercial platform in hepatitis C through expanded global distribution and the addition of complementary products. Our agreements with Valeant achieve milestones for both of these objectives. Taribavirin completes our ribavirin franchise and will ensure its future sustainability and growth. We have also expanded our global distribution network for ribavirin into markets in which Valeant is a leading provider."
Taribavirin and ribavirin are both nucleoside antimetabolite drugs that interfere with duplication of viral genetic material. Ribavirin is currently indicated, either alone or in combination with other therapies, for hepatitis C infection and other viral infections. Ribasphere(R) and Ribapak(R), proprietary formulations of ribavirin, are currently marketed by Kadmon's Three Rivers Pharmaceuticals division for the treatment of hepatitis C in territories around the world.
Taribavirin is a prodrug of ribavirin currently in development for the treatment of chronic hepatitis C. Data from a Phase IIb weight-based dosing study presented at the American Association for the Study of Liver Disease 2009 Annual Meeting demonstrated similar efficacy to ribavirin but with significantly less anemia, which is the main treatment-limiting toxicity associated with ribavirin.
About Valeant Pharmaceuticals International, Inc.
Valeant Pharmaceuticals International, Inc. (nyse/tsx:VRX) is a multinational specialty pharmaceutical company that develops, manufactures and markets a broad range of products primarily in the areas of neurology, dermatology and branded generics. More information about Valeant can be found at http://www.valeant.com/.
About Kadmon Pharmaceuticals
Kadmon Pharmaceuticals LLC is a privately held, New York City-based biopharmaceutical company founded on its expertise in novel science. The company explores new understandings in molecular biology to develop therapies that target the metabolomic or signaling pathways associated with disease, including novel anti hepatitis C therapies. Collaborating with academic centers and private enterprise at the forefront of innovation, Kadmon is focused on pioneering medicines in the areas of oncology, infectious diseases and immunology.
Caution Regarding Forward-Looking Information and "Safe Harbor" Statement
To the extent any statements made in this document contain information that is not historical, these statements are forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, and may be forward-looking information as defined under applicable Canadian securities legislation (collectively, "forward-looking statements").
These forward-looking statements relate to, among other things, the strength of our partner, the impact of ribavirin on our branded generic portfolio in Central Europe and the ability of a taribavirin product, if approved, to provide patients with improved treatment. Forward-looking statements can generally be identified by the use of words such as "believe", "anticipate", "expect", "estimate", "intend", "continue", "plan", "project", "will", "may", "should", "could", "would", "target", "potential" and other similar expressions. In addition, any statements that refer to expectations, projections or other characterizations of future events or circumstances are forward-looking statements. Actual results may differ materially from those expressed or implied in such statements. Important factors that could cause actual results to differ materially from these expectations include, among other things, the strength of our partner, the impact of ribavirin on our branded generic portfolio in Central Europe and the ability of a taribavirin product, if approved, to provide patients with improved treatment, and the risk factors as detailed from time to time in Valeant's reports filed with the Securities and Exchange Commission ("SEC") and the Canadian Securities Administrators ("CSA").
Contact Information
For Valeant:
Laurie W. Little
Valeant Pharmaceuticals
949.461.6002
laurie.little@valeant.com
For Kadmon:
David Pitts
Argot Partners
212.600.1902
david@argotpartners.com
Source
Showing posts with label Taribavirin. Show all posts
Showing posts with label Taribavirin. Show all posts
November 1, 2010
September 24, 2010
Taribavirin May Be Safe, Effective for Chronic Hepatitis C
Laurie Barclay, MD
September 24, 2010 — Weight-based taribavirin (TBV) treatment was associated with a reduction in anemia and increased sustained virologic response in treatment-naive patients with genotype 1 chronic hepatitis C virus (HCV) infection, according to the results of a phase 2b, open-label, active-controlled, parallel-group, randomized study published online June 30 and in the October issue of Hepatology.
"Ribavirin [RBV]-induced hemolytic anemia can prompt dose reductions and lower sustained virologic response (SVR) rates in the treatment of patients with chronic hepatitis C," write Fred Poordad, MD, from Cedars-Sinai Medical Center in Los Angeles, California, and colleagues. "The study aimed to determine if weight-based dosing of [TBV], an oral prodrug of [RBV], demonstrated efficacy comparable to RBV while maintaining its previously demonstrated anemia advantage with fixed dose administration."
At 51 centers in the United States between March 2007 and October 2008, 278 treatment-naive patients infected with genotype 1 HCV were stratified by body weight and baseline viral load and randomly assigned 1:1:1:1 to receive TBV (20, 25, or 30 mg/kg/day) or RBV (800 - 1400 mg/day) with pegylated interferon alfa-2b for 48 weeks.
"This study suggests that comparable SVR rates may be achieved with weight based taribavirin and peg interferon in a genotype 1 population," Paul Y. Kwo, MD, associate professor of medicine, Division of Gastroenterology/Hepatology, Indiana University School of Medicine in Indianapolis, and coauthor of an accompanying editorial, published online September 7 and in the October issue of the journal, told Medscape Medical News. "Thus, as we enter the era of direct-acting antiviral agents (DAAs) with PEG interferon and RBV, TBV is an agent that deserves study to see if it can be added to PEG interferon and DAAs to preserve or improve SVR rates with lower rates of anemia. "
This patient population used in this study was considered difficult to cure because of their demographics and clinical characteristics, including high viral load and advanced fibrosis. Mean age was 49 years, 61% were men, 30% were black or Latino, and mean weight was 82 kg.
SVR rates were 28.4%, 24.3%, 20.6%, and 21.4% in the 20-, 25-, and 30-mg/kg TBV groups and the RBV group, respectively. Efficacy analyses showed no statistical differences.
Compared with the RBV groups, the 20- and 25-mg/kg/day TBV treatment groups had significantly lower rates of anemia (32.9%, 13.4%, and 15.7%, respectively; P < .05). In all groups, the most commonly reported adverse events were fatigue, diarrhea, and insomnia. Although diarrhea was reported in 38% of patients receiving TBV compared with 21% of patients receiving RBV, this was generally mild and not dose-limiting.
Fewer patients treated with TBV required dose reductions (13% - 28%) compared with 32% of patients treated with RBV. Less-frequent dose modification in patients treated with TBV may reduce the requirement for use of erythropoiesis-stimulating agents.
"All TBV doses demonstrated efficacy and tolerability comparable to that of RBV; however, the 25 mg/kg dose demonstrated the optimal balance of safety and efficacy," the study authors write. "Anemia rates were significantly lower for TBV given at 20-25 mg/kg than RBV. These data suggest weight-based dosing with TBV provides a safe and effective treatment alternative to RBV for chronic [HCV]."
When asked about study limitations, Dr. Kwo noted that despite the lower anemia rates, the drop-out rate for anemia was similar between TBV and RBV, possibly because of a small sample size.
"There are many populations that have great difficulty tolerating RBV now (those with advanced liver disease, older patients, patients who have undergone liver transplantation, human immunodeficiency virus/HCV-coinfected individuals, and patients with hemoglobulinopathies and chronic renal failure), and these are populations that could potentially benefit from TBV," Dr. Kwo concluded. "[In future studies], TBV should be added to PEG interferon and DAA agents to see if viral response rates can be preserved or improved with lower rates of anemia when compared to PEG interferon, RBV and DAA agents."
Valeant Pharmaceuticals employs 4 of the study authors. The other study authors have disclosed no relevant financial relationships. Dr. Kwo reports receiving grant support from Schering Plough, Merck, Vertex, Valeant, Abbott, Bristol Myers Squibb, Tibotec, Glaxo Smith Kline, and Gilead; consulting for Schering Plough/Merck, Idenix, and Human Genome Sciences; and consulting on the ad boards for Merck, Schering Plough, Vertex, Gilead, Anadys, Abbott, Human Genome Sciences, and Novartis. He also reports speaking and teaching for Schering Plough/Merck, Roche, Gilead, and Bristol-Myers Squibb.
Hepatology. Published online June 30 and September 7, 2010.
Source
Also See:
-- Weight-Based Dosing Best for New HCV Drug
-- Taribavirin Offers a Safe, Effective Alternative for Chronic Hepatitis C, Study Finds
September 24, 2010 — Weight-based taribavirin (TBV) treatment was associated with a reduction in anemia and increased sustained virologic response in treatment-naive patients with genotype 1 chronic hepatitis C virus (HCV) infection, according to the results of a phase 2b, open-label, active-controlled, parallel-group, randomized study published online June 30 and in the October issue of Hepatology.
"Ribavirin [RBV]-induced hemolytic anemia can prompt dose reductions and lower sustained virologic response (SVR) rates in the treatment of patients with chronic hepatitis C," write Fred Poordad, MD, from Cedars-Sinai Medical Center in Los Angeles, California, and colleagues. "The study aimed to determine if weight-based dosing of [TBV], an oral prodrug of [RBV], demonstrated efficacy comparable to RBV while maintaining its previously demonstrated anemia advantage with fixed dose administration."
At 51 centers in the United States between March 2007 and October 2008, 278 treatment-naive patients infected with genotype 1 HCV were stratified by body weight and baseline viral load and randomly assigned 1:1:1:1 to receive TBV (20, 25, or 30 mg/kg/day) or RBV (800 - 1400 mg/day) with pegylated interferon alfa-2b for 48 weeks.
"This study suggests that comparable SVR rates may be achieved with weight based taribavirin and peg interferon in a genotype 1 population," Paul Y. Kwo, MD, associate professor of medicine, Division of Gastroenterology/Hepatology, Indiana University School of Medicine in Indianapolis, and coauthor of an accompanying editorial, published online September 7 and in the October issue of the journal, told Medscape Medical News. "Thus, as we enter the era of direct-acting antiviral agents (DAAs) with PEG interferon and RBV, TBV is an agent that deserves study to see if it can be added to PEG interferon and DAAs to preserve or improve SVR rates with lower rates of anemia. "
This patient population used in this study was considered difficult to cure because of their demographics and clinical characteristics, including high viral load and advanced fibrosis. Mean age was 49 years, 61% were men, 30% were black or Latino, and mean weight was 82 kg.
SVR rates were 28.4%, 24.3%, 20.6%, and 21.4% in the 20-, 25-, and 30-mg/kg TBV groups and the RBV group, respectively. Efficacy analyses showed no statistical differences.
Compared with the RBV groups, the 20- and 25-mg/kg/day TBV treatment groups had significantly lower rates of anemia (32.9%, 13.4%, and 15.7%, respectively; P < .05). In all groups, the most commonly reported adverse events were fatigue, diarrhea, and insomnia. Although diarrhea was reported in 38% of patients receiving TBV compared with 21% of patients receiving RBV, this was generally mild and not dose-limiting.
Fewer patients treated with TBV required dose reductions (13% - 28%) compared with 32% of patients treated with RBV. Less-frequent dose modification in patients treated with TBV may reduce the requirement for use of erythropoiesis-stimulating agents.
"All TBV doses demonstrated efficacy and tolerability comparable to that of RBV; however, the 25 mg/kg dose demonstrated the optimal balance of safety and efficacy," the study authors write. "Anemia rates were significantly lower for TBV given at 20-25 mg/kg than RBV. These data suggest weight-based dosing with TBV provides a safe and effective treatment alternative to RBV for chronic [HCV]."
When asked about study limitations, Dr. Kwo noted that despite the lower anemia rates, the drop-out rate for anemia was similar between TBV and RBV, possibly because of a small sample size.
"There are many populations that have great difficulty tolerating RBV now (those with advanced liver disease, older patients, patients who have undergone liver transplantation, human immunodeficiency virus/HCV-coinfected individuals, and patients with hemoglobulinopathies and chronic renal failure), and these are populations that could potentially benefit from TBV," Dr. Kwo concluded. "[In future studies], TBV should be added to PEG interferon and DAA agents to see if viral response rates can be preserved or improved with lower rates of anemia when compared to PEG interferon, RBV and DAA agents."
Valeant Pharmaceuticals employs 4 of the study authors. The other study authors have disclosed no relevant financial relationships. Dr. Kwo reports receiving grant support from Schering Plough, Merck, Vertex, Valeant, Abbott, Bristol Myers Squibb, Tibotec, Glaxo Smith Kline, and Gilead; consulting for Schering Plough/Merck, Idenix, and Human Genome Sciences; and consulting on the ad boards for Merck, Schering Plough, Vertex, Gilead, Anadys, Abbott, Human Genome Sciences, and Novartis. He also reports speaking and teaching for Schering Plough/Merck, Roche, Gilead, and Bristol-Myers Squibb.
Hepatology. Published online June 30 and September 7, 2010.
Source
Also See:
-- Weight-Based Dosing Best for New HCV Drug
-- Taribavirin Offers a Safe, Effective Alternative for Chronic Hepatitis C, Study Finds
September 23, 2010
Weight-Based Dosing Best for New HCV Drug
By Michael Smith, North American Correspondent, MedPage Today Published: September 23, 2010
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston.
When given in doses based on weight, an investigational prodrug of ribavirin had efficacy comparable to ribavirin in chronic hepatitis C but with less hemolytic anemia, researchers reported.
In a phase IIb trial, the drug -- taribavirin -- yielded early response rates that were statistically identical with those achieved with ribavirin when both drugs were given with pegylated interferon alfa-2b, according to Fred Poordad, MD, of Cedars-Sinai Medical Center in Los Angeles, and colleagues.
At the same time, two of the tested doses of the drug caused significantly less anemia (at P<0.05) than ribavirin, they reported online in Hepatology.
Taribavirin, formerly known as viramidine, is a nucleoside analogue and oral prodrug of ribavirin that is converted to ribavirin in the body. But its structural difference from the older drug means that it is less likely to enter and damage red blood cells, the researchers noted.
Indeed, in earlier studies using a fixed dose of taribavirin, that benefit was demonstrated, but efficacy was inferior to that of ribavirin, they said. Analysis suggested that the fixed-dose approach, as well as selection of inadequate doses, was responsible for the lack of efficacy.
To clarify the issue, Poordad and colleagues tested three doses of taribavirin -- 20, 25, or 30 mg per kilogram a day -- against ribavirin at 800 to 1,400 mg a day in 278 treatment-naïve patients with genotype 1 hepatitis C.
The primary efficacy endpoint was early virologic response, defined as the proportion of patients with at least a two-log decrease from baseline in serum hepatitis C RNA levels after two weeks of therapy. The researchers also looked at sustained virologic response after 48 weeks of therapy.
The main safety endpoint was the proportion of patients with hemoglobin less than 10 grams per deciliter at any time during the study.
The researchers found that:
• 43 patients in the 20-mg/kg (64.2%) had an early virologic response, as did 40 (57.1%) and 37 (54.4%) in the 25- and 30-mg/kg arms.
• At the same time, 36 ribavirin patients (51.4%) had an early virologic response, not significantly different from any of the taribavirin arms.
• Fewer patients on taribavirin required dose reductions (13% to 28%, depending on the dose) compared with 32% of ribavirin.
• The anemia rates were 13.4% and 15.7%, respectively, in the 20- and 30-mg/kg taribavirin arms, compared with 32.9% among ribavirin patients, significantly different at P<0.05 in both cases.
All told, 41% of patients in the three taribavirin arms completed treatment and follow-up, compared with 36% of the ribavirin patients, with 29% of those who dropped out citing lack of response as the reason and 20% citing adverse events.
The data suggest the drug "may be an effective agent" to substitute for ribavirin in the future, the researchers concluded.
On the other hand, the treatment picture is changing rapidly and could leave the drug with a "finite life cycle," according to Paul Kwo, MD and Rakesh Vinayek, MBBS, both of Indiana University in Indianapolis.
Taribavirin "may have a role in populations particularly sensitive to ribavirin-related anemia," they said in an accompanying editorial, and might be a "welcome addition" to the list of drugs available to treat hepatitis C.
But several clinical trials are beginning with combinations of direct-acting antiviral agents, with and without pegylated interferon, and protease inhibitors under development could also have lower rates of anemia, they said.
For those reasons, "the role of (taribavirin) remains less precisely defined," they argued.
The study was supported by Valeant Pharmaceuticals, which is developing the drug.
Poordad said he had no financial conflicts to report. Several authors are employees of the company.
Primary source: Hepatology
Source reference:
Poordad F, et al. "Virologic response rates of weight-based taribavirin versus ribavirin in treatment-naive patients with genotype 1 chronic hepatitis C" Hepatology 2010; DOI: 10.1002/hep.23827.
Additional source: Hepatology
Source reference:
Kwo PY, Vinayek R. "The next step for taribavirin" Hepatology 2010; DOI: 10.1002/hep.2395.
Source
Also See: Taribavirin Offers a Safe, Effective Alternative for Chronic Hepatitis C, Study Finds
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston.
When given in doses based on weight, an investigational prodrug of ribavirin had efficacy comparable to ribavirin in chronic hepatitis C but with less hemolytic anemia, researchers reported.
In a phase IIb trial, the drug -- taribavirin -- yielded early response rates that were statistically identical with those achieved with ribavirin when both drugs were given with pegylated interferon alfa-2b, according to Fred Poordad, MD, of Cedars-Sinai Medical Center in Los Angeles, and colleagues.
At the same time, two of the tested doses of the drug caused significantly less anemia (at P<0.05) than ribavirin, they reported online in Hepatology.
Taribavirin, formerly known as viramidine, is a nucleoside analogue and oral prodrug of ribavirin that is converted to ribavirin in the body. But its structural difference from the older drug means that it is less likely to enter and damage red blood cells, the researchers noted.
Indeed, in earlier studies using a fixed dose of taribavirin, that benefit was demonstrated, but efficacy was inferior to that of ribavirin, they said. Analysis suggested that the fixed-dose approach, as well as selection of inadequate doses, was responsible for the lack of efficacy.
To clarify the issue, Poordad and colleagues tested three doses of taribavirin -- 20, 25, or 30 mg per kilogram a day -- against ribavirin at 800 to 1,400 mg a day in 278 treatment-naïve patients with genotype 1 hepatitis C.
The primary efficacy endpoint was early virologic response, defined as the proportion of patients with at least a two-log decrease from baseline in serum hepatitis C RNA levels after two weeks of therapy. The researchers also looked at sustained virologic response after 48 weeks of therapy.
The main safety endpoint was the proportion of patients with hemoglobin less than 10 grams per deciliter at any time during the study.
The researchers found that:
• 43 patients in the 20-mg/kg (64.2%) had an early virologic response, as did 40 (57.1%) and 37 (54.4%) in the 25- and 30-mg/kg arms.
• At the same time, 36 ribavirin patients (51.4%) had an early virologic response, not significantly different from any of the taribavirin arms.
• Fewer patients on taribavirin required dose reductions (13% to 28%, depending on the dose) compared with 32% of ribavirin.
• The anemia rates were 13.4% and 15.7%, respectively, in the 20- and 30-mg/kg taribavirin arms, compared with 32.9% among ribavirin patients, significantly different at P<0.05 in both cases.
All told, 41% of patients in the three taribavirin arms completed treatment and follow-up, compared with 36% of the ribavirin patients, with 29% of those who dropped out citing lack of response as the reason and 20% citing adverse events.
The data suggest the drug "may be an effective agent" to substitute for ribavirin in the future, the researchers concluded.
On the other hand, the treatment picture is changing rapidly and could leave the drug with a "finite life cycle," according to Paul Kwo, MD and Rakesh Vinayek, MBBS, both of Indiana University in Indianapolis.
Taribavirin "may have a role in populations particularly sensitive to ribavirin-related anemia," they said in an accompanying editorial, and might be a "welcome addition" to the list of drugs available to treat hepatitis C.
But several clinical trials are beginning with combinations of direct-acting antiviral agents, with and without pegylated interferon, and protease inhibitors under development could also have lower rates of anemia, they said.
For those reasons, "the role of (taribavirin) remains less precisely defined," they argued.
The study was supported by Valeant Pharmaceuticals, which is developing the drug.
Poordad said he had no financial conflicts to report. Several authors are employees of the company.
Primary source: Hepatology
Source reference:
Poordad F, et al. "Virologic response rates of weight-based taribavirin versus ribavirin in treatment-naive patients with genotype 1 chronic hepatitis C" Hepatology 2010; DOI: 10.1002/hep.23827.
Additional source: Hepatology
Source reference:
Kwo PY, Vinayek R. "The next step for taribavirin" Hepatology 2010; DOI: 10.1002/hep.2395.
Source
Also See: Taribavirin Offers a Safe, Effective Alternative for Chronic Hepatitis C, Study Finds
September 22, 2010
Taribavirin Offers a Safe, Effective Alternative for Chronic Hepatitis C, Study Finds
ScienceDaily (Sep. 22, 2010) — Researchers at Cedars-Sinai Medical Center and 50 other centers found that weight-based dosing of taribavirin reduces rates of anemia while increasing sustained virologic response (SVR) in patients with chronic hepatitis C (HCV). Full details of this study are available in the October issue of Hepatology, a journal published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases (AASLD).
Chronic HCV is typically treated with ribavirin (RBV). When used in combination with peginterferon alfa (peg-IFN), RBV significantly enhances on-treatment virologic response and reduces relapse. However, RBV, particularly the combination of interferon and RBV, is associated with hemolytic anemia, a significant toxicity resulting from the accumulation of RBV in red blood cells. Taribavirin (TBV), formerly known as viramidine, is a nucleoside analog and oral pro-drug of RBV that is less able to enter red blood cells, and should therefore be associated with significantly less anemia.
This theory was demonstrated in two previous phase 3 trials. While statistically less anemia was observed in patients treated with TBV compared to RBV, the primary efficacy endpoint of these studies, a non-inferior SVR between the TBV and RBV, was not achieved. Detailed subgroup analyses of the data suggest fixed dosing as opposed to weight-based dosing, and the selection of an inadequate dose, are to blame. The present multi-center study explored several higher weight-based doses of TBV to determine a dosage regimen that was able to deliver comparable responses to RBV with fewer incidences of anemia.
A phase 2b randomized, open-label, active-controlled, parallel-group study was conducted in 278 treatment-naïve, genotype 1 patients stratified by body weight and baseline viral load at 51 centers in the United States between March 2007 and October 2008. Patients were randomized 1:1:1:1 to receive TBV (20, 25, or 30 mg/kg/day) or RBV (800 -1400 mg/day) with pegylated interferon alfa-2b for 48 weeks.
The primary efficacy endpoint was early virologic response (EVR) defined as the proportion of patients with at least a 2-log decrease from baseline in serum HCV RNA levels at treatment week 12. Additional efficacy endpoints included SVR, undetectable HCV RNA at treatment weeks 4, 24 and 48, and viral relapse for those who were responders at the end of treatment. A total of 86 (41%) of TBV patients and 25 (36%) of the RBV group completed treatment and follow up. The most commonly cited reasons for premature withdrawal were lack of response (29%) and adverse events (20%).
The present study demonstrated that weight-based dosing of TBV achieved comparable efficacy to RBV as demonstrated by SVR. This was observed in all three TBV weight-based dose treatment groups, which met the study's primary end-point. Patients treated with TBV had less than half the anemia compared to RBV treated patients. These results suggest weight-based dosing of TBV can significantly improve the tolerability of HCV treatment while maintaining efficacy. Specifically, the 25 mg/kg dose offered the optimal balance of efficacy and safety in this patient population.
Notably, fewer patients treated with TBV required dose reductions (13-28%) compared to 32% of patients treated with RBV. Less frequent dose modification in patients treated with TBV may alleviate the need to utilize erythropoiesis-stimulating agents (ESAs). Several studies have demonstrated the use of ESAs can significantly decrease the need to dose reduce RBV and leads to an improvement in the quality of life during HCV treatment, but fails to improve the SVR. The use of ESAs also adds significant cost to HCV treatment and is associated with serious adverse events including thrombosis and red cell aplasia.
Lead investigator Dr. Fred Poordad concludes, "These data suggest TBV may be an effective agent to substitute for RBV in the future and could be incorporated in upcoming trials utilizing emerging small molecules for HCV treatment."
Editorial author Dr. Paul Kwo comments, "If TBV can be shown to preserve or improve efficacy rates in combination with direct-acting antiviral agents (DAAs) and Peg IFN, with lower rates of anemia, the use of TBV in these clinical settings would be a welcome addition to the HCV armamentarium as we begin to expand the HCV populations that we treat. TBV may have a role in populations particularly sensitive to ribavirin-related anemia. However, with the commencement of several trials comprising of multiple combinations of DAAs with and without pegIFN/RBV, and the development of newer protease inhibitors with potentially lower rates of anemia, the role of TBV remains less precisely defined and could potentially have a finite life cycle."
Source
Chronic HCV is typically treated with ribavirin (RBV). When used in combination with peginterferon alfa (peg-IFN), RBV significantly enhances on-treatment virologic response and reduces relapse. However, RBV, particularly the combination of interferon and RBV, is associated with hemolytic anemia, a significant toxicity resulting from the accumulation of RBV in red blood cells. Taribavirin (TBV), formerly known as viramidine, is a nucleoside analog and oral pro-drug of RBV that is less able to enter red blood cells, and should therefore be associated with significantly less anemia.
This theory was demonstrated in two previous phase 3 trials. While statistically less anemia was observed in patients treated with TBV compared to RBV, the primary efficacy endpoint of these studies, a non-inferior SVR between the TBV and RBV, was not achieved. Detailed subgroup analyses of the data suggest fixed dosing as opposed to weight-based dosing, and the selection of an inadequate dose, are to blame. The present multi-center study explored several higher weight-based doses of TBV to determine a dosage regimen that was able to deliver comparable responses to RBV with fewer incidences of anemia.
A phase 2b randomized, open-label, active-controlled, parallel-group study was conducted in 278 treatment-naïve, genotype 1 patients stratified by body weight and baseline viral load at 51 centers in the United States between March 2007 and October 2008. Patients were randomized 1:1:1:1 to receive TBV (20, 25, or 30 mg/kg/day) or RBV (800 -1400 mg/day) with pegylated interferon alfa-2b for 48 weeks.
The primary efficacy endpoint was early virologic response (EVR) defined as the proportion of patients with at least a 2-log decrease from baseline in serum HCV RNA levels at treatment week 12. Additional efficacy endpoints included SVR, undetectable HCV RNA at treatment weeks 4, 24 and 48, and viral relapse for those who were responders at the end of treatment. A total of 86 (41%) of TBV patients and 25 (36%) of the RBV group completed treatment and follow up. The most commonly cited reasons for premature withdrawal were lack of response (29%) and adverse events (20%).
The present study demonstrated that weight-based dosing of TBV achieved comparable efficacy to RBV as demonstrated by SVR. This was observed in all three TBV weight-based dose treatment groups, which met the study's primary end-point. Patients treated with TBV had less than half the anemia compared to RBV treated patients. These results suggest weight-based dosing of TBV can significantly improve the tolerability of HCV treatment while maintaining efficacy. Specifically, the 25 mg/kg dose offered the optimal balance of efficacy and safety in this patient population.
Notably, fewer patients treated with TBV required dose reductions (13-28%) compared to 32% of patients treated with RBV. Less frequent dose modification in patients treated with TBV may alleviate the need to utilize erythropoiesis-stimulating agents (ESAs). Several studies have demonstrated the use of ESAs can significantly decrease the need to dose reduce RBV and leads to an improvement in the quality of life during HCV treatment, but fails to improve the SVR. The use of ESAs also adds significant cost to HCV treatment and is associated with serious adverse events including thrombosis and red cell aplasia.
Lead investigator Dr. Fred Poordad concludes, "These data suggest TBV may be an effective agent to substitute for RBV in the future and could be incorporated in upcoming trials utilizing emerging small molecules for HCV treatment."
Editorial author Dr. Paul Kwo comments, "If TBV can be shown to preserve or improve efficacy rates in combination with direct-acting antiviral agents (DAAs) and Peg IFN, with lower rates of anemia, the use of TBV in these clinical settings would be a welcome addition to the HCV armamentarium as we begin to expand the HCV populations that we treat. TBV may have a role in populations particularly sensitive to ribavirin-related anemia. However, with the commencement of several trials comprising of multiple combinations of DAAs with and without pegIFN/RBV, and the development of newer protease inhibitors with potentially lower rates of anemia, the role of TBV remains less precisely defined and could potentially have a finite life cycle."
Source
August 1, 2010
Virologic response rates of weight-based taribavirin versus ribavirin in naïve chronic hepatitis C genotype 1 patients
Hepatology
Volume 9999 Issue 999A, Page NA
Published Online: 30 Jun 2010
Copyright © 2010 American Association for the Study of Liver Diseases
F Poordad 1 *, E Lawitz 2, ML Shiffman 3, T Hassanein 4, AJ Muir 5, B Bacon 6, J Heise 7, D Halliman 7, E Chun 7, J Hammond 7
1 Cedars-Sinai Medical Center, Los Angeles, CA, USA
2 Alamo Medical Research, San Antonio, TX, USA
3 McGuire Research Institute, McGuire Veterans Administration Medical Center, Richmond, VA, USA
4 Southern California Liver Centers, San Clemente, CA, USA
5 Duke Clinical Research Institute, Duke University, Durham, NC, USA
6 Saint Louis University School of Medicine, St. Louis, MO, USA
7 Valeant Pharmaceuticals North America, Aliso Viejo, CA, USA
email: F Poordad (fred.poordad@cshs.org)
*Correspondence to F Poordad, Cedars -Sinai Medical Center, Hepatology and Liver Transplantation, Los Angeles, California, United States
Keywords
anemia • erythropoiesis-stimulating agents • weight-based dosing • antiviral dosing • clinical trial
Abstract
BACKGROUND:
Ribavirin-induced hemolytic anemia can prompt dose reductions and lower sustained virologic response (SVR) rates in the treatment of chronic hepatitis C patients.
The study aimed to determine if weight-based dosing (WBD) of taribavirin (TBV), an oral pro-drug of ribavirin (RBV), demonstrated efficacy comparable to RBV while maintaining its previously demonstrated anemia advantage with fixed dose administration.
METHODS:
A US phase 2b randomized, open-label, active-controlled, parallel-group study was conducted in 278 treatment-naïve, genotype 1 patients stratified by body weight and baseline viral load. Patients were randomized 1:1:1:1 to receive TBV (20, 25, or 30 mg/kg/day) or RBV (800 -1400 mg/day) with pegylated interferon alfa-2b for 48 weeks.
RESULTS:
The SVR rates in this difficult to cure patient demographics (mean age 49 yrs; 61% male; 30% African-American or Latino; high viral load; advanced fibrosis; and mean weight 82 kg) were 28.4%, 24.3%, 20.6% and 21.4% in the 20, 25, 30 mg/kg TBV groups and RBV group, respectively. There were no statistical differences in the efficacy analyses. Anemia rates were significantly lower (p<0.05) in the 20 and 25 mg/kg/day TBV treatment groups (13.4% and 15.7% respectively) compared to RBV (32.9%). The most common adverse events in all groups were fatigue, diarrhea, and insomnia. Diarrhea, reported in 38% of TBV patients versus 21% of RBV patients, was generally mild and not dose-limiting.
CONCLUSIONS:
All TBV doses demonstrated efficacy and tolerability comparable to that of RBV, however the 25 mg/kg dose demonstrated the optimal balance of safety and efficacy. Anemia rates were significantly lower for TBV 20-25 mg/kg than RBV. These data suggest WBD with TBV provides a safe and effective treatment alternative to RBV for chronic hepatitis C. (HEPATOLOGY 2010.)
Received: 24 April 2010; Revised: 18 June 2010; Accepted: 22 June 2010
Digital Object Identifier (DOI)
10.1002/hep.23827 About DOI
Source
Volume 9999 Issue 999A, Page NA
Published Online: 30 Jun 2010
Copyright © 2010 American Association for the Study of Liver Diseases
F Poordad 1 *, E Lawitz 2, ML Shiffman 3, T Hassanein 4, AJ Muir 5, B Bacon 6, J Heise 7, D Halliman 7, E Chun 7, J Hammond 7
1 Cedars-Sinai Medical Center, Los Angeles, CA, USA
2 Alamo Medical Research, San Antonio, TX, USA
3 McGuire Research Institute, McGuire Veterans Administration Medical Center, Richmond, VA, USA
4 Southern California Liver Centers, San Clemente, CA, USA
5 Duke Clinical Research Institute, Duke University, Durham, NC, USA
6 Saint Louis University School of Medicine, St. Louis, MO, USA
7 Valeant Pharmaceuticals North America, Aliso Viejo, CA, USA
email: F Poordad (fred.poordad@cshs.org)
*Correspondence to F Poordad, Cedars -Sinai Medical Center, Hepatology and Liver Transplantation, Los Angeles, California, United States
Keywords
anemia • erythropoiesis-stimulating agents • weight-based dosing • antiviral dosing • clinical trial
Abstract
BACKGROUND:
Ribavirin-induced hemolytic anemia can prompt dose reductions and lower sustained virologic response (SVR) rates in the treatment of chronic hepatitis C patients.
The study aimed to determine if weight-based dosing (WBD) of taribavirin (TBV), an oral pro-drug of ribavirin (RBV), demonstrated efficacy comparable to RBV while maintaining its previously demonstrated anemia advantage with fixed dose administration.
METHODS:
A US phase 2b randomized, open-label, active-controlled, parallel-group study was conducted in 278 treatment-naïve, genotype 1 patients stratified by body weight and baseline viral load. Patients were randomized 1:1:1:1 to receive TBV (20, 25, or 30 mg/kg/day) or RBV (800 -1400 mg/day) with pegylated interferon alfa-2b for 48 weeks.
RESULTS:
The SVR rates in this difficult to cure patient demographics (mean age 49 yrs; 61% male; 30% African-American or Latino; high viral load; advanced fibrosis; and mean weight 82 kg) were 28.4%, 24.3%, 20.6% and 21.4% in the 20, 25, 30 mg/kg TBV groups and RBV group, respectively. There were no statistical differences in the efficacy analyses. Anemia rates were significantly lower (p<0.05) in the 20 and 25 mg/kg/day TBV treatment groups (13.4% and 15.7% respectively) compared to RBV (32.9%). The most common adverse events in all groups were fatigue, diarrhea, and insomnia. Diarrhea, reported in 38% of TBV patients versus 21% of RBV patients, was generally mild and not dose-limiting.
CONCLUSIONS:
All TBV doses demonstrated efficacy and tolerability comparable to that of RBV, however the 25 mg/kg dose demonstrated the optimal balance of safety and efficacy. Anemia rates were significantly lower for TBV 20-25 mg/kg than RBV. These data suggest WBD with TBV provides a safe and effective treatment alternative to RBV for chronic hepatitis C. (HEPATOLOGY 2010.)
Received: 24 April 2010; Revised: 18 June 2010; Accepted: 22 June 2010
Digital Object Identifier (DOI)
10.1002/hep.23827 About DOI
Source
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