Showing posts with label PhD. Show all posts
Showing posts with label PhD. Show all posts
Monday, March 5, 2012
Clinical Care Options: "Importance of Pharmacokinetics and Adherence to Avoid Emergence of Resistant HCV Variants"
A new CCO module is available here, focusing on the importance of PK and compliance to regimens in an effort to stem HCV resistance. The parallels between HCV antivirals and the evolution of HIV antiretrovirals are becoming numerous. Pharmacokinetics, pharmacogenetics and pharmacodynamics will all increase in importance as HCV drug development marketplace continues to move forward and potentially become as competitive as the HIV marketplace was back in the mid-90's and 2000's.
Monday, December 5, 2011
Achillion Pharmaceuticals announces preliminary proof-of-concept data with HCV NS5A inhibitor ACH-2928...
Looks like Achillion Pharmaceuticals' NS5A inhibitor is bearing fruit, with the company releasing three-day monotherapy proof-of-concept data for it's first generation NS5A inhibitor ACH-2928 as well as naming a second generation compound ACH-3102, which is slated for early trials in Q1/Q2 next year. CE0 Michael D. Kishbauch is aiming for "a proprietary interferon-free DAA combination regimen for the treatment of HCV within Achillion's pipeline." Looks like Achillion will have plenty to present at EASL 2012, as well as an intention to evaluate an all-oral comb including one of their protease inhibitors and an NS5A inhibitors.
Achillion Announces Preliminary Phase 1b Proof-of-Concept Data With ACH-2928 NS5A Inhibitor for the Treatment of Hepatitis C
Achieves 3.68 Log10 Reduction in HCV RNA After Three Days of Treatment
NEW HAVEN, Conn., Dec 5, 2011 (GlobeNewswire via COMTEX) -- Achillion Pharmaceuticals, Inc. ACHN +1.61% , a leader in the discovery and development of small molecule drugs to combat the most challenging infectious diseases, today reported proof-of-concept data from its Phase 1b clinical trial of ACH-2928, a first-generation NS5A inhibitor, demonstrating that patients treated with ACH-2928 achieved a mean maximum 3.68 log10 reduction in HCV RNA after three-day monotherapy of 60 mg once daily. The compound also demonstrated good safety and tolerability both in healthy volunteers and in patients with chronic hepatitis C (HCV).
ACH-2928, Achillion's first generation inhibitor of the NS5A protein, was discovered through the Company's NS5A inhibitor program. Achillion also recently nominated a second-generation NS5A inhibitor, ACH-3102, which is currently undergoing IND-enabling studies and is expected to be advanced into clinical trials during the first half of 2012.
"We believe NS5A inhibitors have emerged as an important component for an all-oral, direct acting antiviral (DAA) regimen," commented Michael D. Kishbauch, President and Chief Executive Officer of Achillion. "Furthermore, NS5A inhibitors, when combined with a protease inhibitor, have achieved sustained viral responses in clinical trials in tough to treat genotype 1 HCV populations. We believe this highlights the potential to form a proprietary interferon-free DAA combination regimen for the treatment of HCV within Achillion's pipeline."
ACH-2928 Phase 1 Program
In July 2011, Achillion initiated dosing in a randomized, double-blind, placebo-controlled phase 1a/1b clinical trial to investigate the safety, tolerability, pharmacokinetic profile and antiviral activity of ACH-2928. The trial consists of three segments: assessment of single ascending oral doses (SAD) in healthy volunteers, evaluation of 3 days of oral repeat doses in subjects with genotype 1a or 1b HCV, and a 5-day multiple ascending doses segment in healthy volunteers.
During the oral repeat doses segment in subjects infected with HCV, a total of 10 patients were enrolled with 2 patients (genotype 1a) receiving placebo and 8 patients (7 genotype 1a and 1 genotype 1b) treated with 3 doses of 60 mg ACH-2928 administered once daily. No serious adverse events (SAE) were reported and there were no patient discontinuations during treatment. The mean maximum HCV RNA decline during therapy was 3.68 log10 compared to a 0.54 log10 decline for patients receiving placebo. There were no viral breakthroughs observed during ACH-2928 monotherapy.
Preliminary data from the SAD trial segment demonstrated ACH-2928 was well tolerated at all doses evaluated up to and including the maximum dose of 500 mg. There were no serious adverse events, no clinically significant changes in vital signs, electrocardiograms (ECGs), or laboratory evaluations. All reported adverse events were classified as mild or moderate, and were transient in nature.
Based upon these preliminary results, the ongoing Phase 1 study will continue to evaluate the pharmacokinetic, pharmacodynamic, and antiviral profile of ACH-2928. These Phase 1 results have been submitted for presentation at a medical meeting being held during the second quarter of 2012. In parallel, Achillion is advancing its second generation NS5A inhibitor ACH-3102 through IND-enabling studies and the Company expects to initiate clinical development during the first half of 2012.
"As we continue to evaluate ACH-2928 in this Phase 1 study, we are also working rapidly to advance ACH-3102, which has shown in preclinical studies to possess the same potent activity against genotype 1a HCV as ACH-2928, as well as enhanced activity against resistant HCV mutants that have been observed in this patient population," stated Milind Deshpande, PhD, President of Research and Development and Chief Scientific Officer. "We believe these results validate our NS5A development program, and look forward to developing an all-oral combination for clinical evaluation that includes one of our protease inhibitors and an NS5A inhibitor next year."
About NS5A Inhibitors
The NS5A protein is a clinically validated target that serves multiple functions at various stages of the HCV life cycle including involvement in virion production, interaction with host proteins and association with interferon-resistance. Achillion's NS5A inhibitors, including ACH-2928 and ACH-3102, possess potent in vitro activity against all HCV genotypes and demonstrate, in preclinical studies, additive to synergistic activity when combined with NS3 protease inhibitors, NS5B polymerase inhibitors, and ribavirin. In preclinical studies, ACH-2928 and ACH-3102 have demonstrated excellent potency, in the pico-molar range, against HCV RNA replication, including potent activity against genotype 1a while ACH-3102 has been shown to possess enhanced activity against recognized genotype 1 resistant variants.
About HCV
The hepatitis C virus infects the liver and is the most common cause of viral hepatitis, which is an inflammation of the liver. It is currently estimated that more than 170 million people are infected with HCV worldwide and The American Association of Liver Disease estimates that up to 80 percent of individuals become chronically infected following exposure to the virus. If left untreated, chronic hepatitis can lead to permanent liver damage, which can result in the development of liver cancer, liver failure or death. Few therapeutic options currently exist for the treatment of HCV infection. The current standard of care is limited by its specificity for certain types of HCV, significant side-effect profile, and injectable route of administration.
About Achillion Pharmaceuticals
Achillion is an innovative pharmaceutical company dedicated to bringing important new treatments to patients with infectious disease. Achillion's proven discovery and development teams have advanced multiple product candidates with novel mechanisms of action. Achillion is focused on solutions for the most challenging problems in infectious disease including hepatitis C and resistant bacterial infections. For more information on Achillion Pharmaceuticals, please visit www.achillion.com or call 1-203-624-7000.
Forward-Looking Statements
This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other important factors, including statements with respect to the potency, safety and other characteristics of Achillion's NS5A inhibitors, which may not be duplicated in clinical studies, and Achillion's expectations regarding results, timing and duration of clinical trials and reporting of results from clinical trials of Achillion's NS5A inhibitors. Among the important factors that could cause actual results to differ materially from those indicated by such forward-looking statements are risks relating to: Achillion's ability to advance the development of its drug candidates under the timelines it anticipates in current and future clinical trials; to obtain patent protection for its drug candidates, and the freedom to operate under third party intellectual property; to establish commercial manufacturing arrangements and to identify, enter into and maintain collaboration agreements with appropriate third-parties; and to raise the substantial additional capital needed to achieve its business objectives. These and other risks are described in the reports filed by Achillion with the U.S. Securities and Exchange Commission, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2010 and its subsequent SEC filings.
In addition, any forward-looking statement in this press release represents Achillion's views only as of the date of this press release and should not be relied upon as representing its views as of any subsequent date. Achillion disclaims any obligation to update any forward-looking statement, except as required by applicable law.
This news release was distributed by GlobeNewswire, www.globenewswire.com
SOURCE: Achillion Pharmaceuticals, Inc.
CONTACT: Glenn Schulman
Achillion Pharmaceuticals, Inc.
Tel. (203) 752-5510
gschulman@achillion.com
Investors:
Mary Kay Fenton
Achillion Pharmaceuticals, Inc.
Tel. (203) 624-7000
mfenton@achillion.com
Media:
Christin Culotta Miller
Ogilvy PR
Tel. (212) 880-5264
christin.miller@ogilvy.com
Achillion Announces Preliminary Phase 1b Proof-of-Concept Data With ACH-2928 NS5A Inhibitor for the Treatment of Hepatitis C
Achieves 3.68 Log10 Reduction in HCV RNA After Three Days of Treatment
NEW HAVEN, Conn., Dec 5, 2011 (GlobeNewswire via COMTEX) -- Achillion Pharmaceuticals, Inc. ACHN +1.61% , a leader in the discovery and development of small molecule drugs to combat the most challenging infectious diseases, today reported proof-of-concept data from its Phase 1b clinical trial of ACH-2928, a first-generation NS5A inhibitor, demonstrating that patients treated with ACH-2928 achieved a mean maximum 3.68 log10 reduction in HCV RNA after three-day monotherapy of 60 mg once daily. The compound also demonstrated good safety and tolerability both in healthy volunteers and in patients with chronic hepatitis C (HCV).
ACH-2928, Achillion's first generation inhibitor of the NS5A protein, was discovered through the Company's NS5A inhibitor program. Achillion also recently nominated a second-generation NS5A inhibitor, ACH-3102, which is currently undergoing IND-enabling studies and is expected to be advanced into clinical trials during the first half of 2012.
"We believe NS5A inhibitors have emerged as an important component for an all-oral, direct acting antiviral (DAA) regimen," commented Michael D. Kishbauch, President and Chief Executive Officer of Achillion. "Furthermore, NS5A inhibitors, when combined with a protease inhibitor, have achieved sustained viral responses in clinical trials in tough to treat genotype 1 HCV populations. We believe this highlights the potential to form a proprietary interferon-free DAA combination regimen for the treatment of HCV within Achillion's pipeline."
ACH-2928 Phase 1 Program
In July 2011, Achillion initiated dosing in a randomized, double-blind, placebo-controlled phase 1a/1b clinical trial to investigate the safety, tolerability, pharmacokinetic profile and antiviral activity of ACH-2928. The trial consists of three segments: assessment of single ascending oral doses (SAD) in healthy volunteers, evaluation of 3 days of oral repeat doses in subjects with genotype 1a or 1b HCV, and a 5-day multiple ascending doses segment in healthy volunteers.
During the oral repeat doses segment in subjects infected with HCV, a total of 10 patients were enrolled with 2 patients (genotype 1a) receiving placebo and 8 patients (7 genotype 1a and 1 genotype 1b) treated with 3 doses of 60 mg ACH-2928 administered once daily. No serious adverse events (SAE) were reported and there were no patient discontinuations during treatment. The mean maximum HCV RNA decline during therapy was 3.68 log10 compared to a 0.54 log10 decline for patients receiving placebo. There were no viral breakthroughs observed during ACH-2928 monotherapy.
Preliminary data from the SAD trial segment demonstrated ACH-2928 was well tolerated at all doses evaluated up to and including the maximum dose of 500 mg. There were no serious adverse events, no clinically significant changes in vital signs, electrocardiograms (ECGs), or laboratory evaluations. All reported adverse events were classified as mild or moderate, and were transient in nature.
Based upon these preliminary results, the ongoing Phase 1 study will continue to evaluate the pharmacokinetic, pharmacodynamic, and antiviral profile of ACH-2928. These Phase 1 results have been submitted for presentation at a medical meeting being held during the second quarter of 2012. In parallel, Achillion is advancing its second generation NS5A inhibitor ACH-3102 through IND-enabling studies and the Company expects to initiate clinical development during the first half of 2012.
"As we continue to evaluate ACH-2928 in this Phase 1 study, we are also working rapidly to advance ACH-3102, which has shown in preclinical studies to possess the same potent activity against genotype 1a HCV as ACH-2928, as well as enhanced activity against resistant HCV mutants that have been observed in this patient population," stated Milind Deshpande, PhD, President of Research and Development and Chief Scientific Officer. "We believe these results validate our NS5A development program, and look forward to developing an all-oral combination for clinical evaluation that includes one of our protease inhibitors and an NS5A inhibitor next year."
About NS5A Inhibitors
The NS5A protein is a clinically validated target that serves multiple functions at various stages of the HCV life cycle including involvement in virion production, interaction with host proteins and association with interferon-resistance. Achillion's NS5A inhibitors, including ACH-2928 and ACH-3102, possess potent in vitro activity against all HCV genotypes and demonstrate, in preclinical studies, additive to synergistic activity when combined with NS3 protease inhibitors, NS5B polymerase inhibitors, and ribavirin. In preclinical studies, ACH-2928 and ACH-3102 have demonstrated excellent potency, in the pico-molar range, against HCV RNA replication, including potent activity against genotype 1a while ACH-3102 has been shown to possess enhanced activity against recognized genotype 1 resistant variants.
About HCV
The hepatitis C virus infects the liver and is the most common cause of viral hepatitis, which is an inflammation of the liver. It is currently estimated that more than 170 million people are infected with HCV worldwide and The American Association of Liver Disease estimates that up to 80 percent of individuals become chronically infected following exposure to the virus. If left untreated, chronic hepatitis can lead to permanent liver damage, which can result in the development of liver cancer, liver failure or death. Few therapeutic options currently exist for the treatment of HCV infection. The current standard of care is limited by its specificity for certain types of HCV, significant side-effect profile, and injectable route of administration.
About Achillion Pharmaceuticals
Achillion is an innovative pharmaceutical company dedicated to bringing important new treatments to patients with infectious disease. Achillion's proven discovery and development teams have advanced multiple product candidates with novel mechanisms of action. Achillion is focused on solutions for the most challenging problems in infectious disease including hepatitis C and resistant bacterial infections. For more information on Achillion Pharmaceuticals, please visit www.achillion.com or call 1-203-624-7000.
Forward-Looking Statements
This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other important factors, including statements with respect to the potency, safety and other characteristics of Achillion's NS5A inhibitors, which may not be duplicated in clinical studies, and Achillion's expectations regarding results, timing and duration of clinical trials and reporting of results from clinical trials of Achillion's NS5A inhibitors. Among the important factors that could cause actual results to differ materially from those indicated by such forward-looking statements are risks relating to: Achillion's ability to advance the development of its drug candidates under the timelines it anticipates in current and future clinical trials; to obtain patent protection for its drug candidates, and the freedom to operate under third party intellectual property; to establish commercial manufacturing arrangements and to identify, enter into and maintain collaboration agreements with appropriate third-parties; and to raise the substantial additional capital needed to achieve its business objectives. These and other risks are described in the reports filed by Achillion with the U.S. Securities and Exchange Commission, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2010 and its subsequent SEC filings.
In addition, any forward-looking statement in this press release represents Achillion's views only as of the date of this press release and should not be relied upon as representing its views as of any subsequent date. Achillion disclaims any obligation to update any forward-looking statement, except as required by applicable law.
This news release was distributed by GlobeNewswire, www.globenewswire.com
SOURCE: Achillion Pharmaceuticals, Inc.
CONTACT: Glenn Schulman
Achillion Pharmaceuticals, Inc.
Tel. (203) 752-5510
gschulman@achillion.com
Investors:
Mary Kay Fenton
Achillion Pharmaceuticals, Inc.
Tel. (203) 624-7000
mfenton@achillion.com
Media:
Christin Culotta Miller
Ogilvy PR
Tel. (212) 880-5264
christin.miller@ogilvy.com
Friday, November 18, 2011
Medscape article: Adverse CNS Effects of HCV Treatment Discourage Adherence
Medscape interviews clinical psychologist Jeffrey J. Weiss, PhD, MS, from Mount Sinai School of Medicine in New York City and Raymond Chung, MD,vice chief of the gastrointestinal unit and medical director of the liver transplant program at Massachusetts General Hospital in Boston regarding a large prospective study looking at CNS effects of Peg + riba and the resulting effect on adherence because of depression and/or 'brain fog'.
Adverse CNS Effects of HCV Treatment Discourage Adherence
Neil Canavan
November 18, 2011 (San Francisco, California) — Patients infected with hepatitis C virus (HCV) can experience a marked decline in neuropsychological cognitive function in the first 14 weeks of combination pegylated interferon and ribavirin therapy. This poses a potential treat to treatment adherence, said clinical psychologist Jeffrey J. Weiss, PhD, MS, from Mount Sinai School of Medicine in New York City, here at The Liver Meeting 2011: American Association for the Study of Liver Diseases 62nd Annual Meeting.
These data are from a large prospective study looking at early treatment discontinuation and the onset of neuropsychiatric symptomatology in HCV monoinfected and HCV/HIV coinfected treatment-naïve patients receiving combination pegylated interferon/ribavirin therapy, Dr. Weiss explained.
"A lot of work has focused on depression, and not to the decrements in cognitive function," said Dr. Weiss. A host of neuropsychiatric symptoms should be considered when initiating a new treatment.
"In this era of direct-acting antivirals, when we're asking patients to take medications 3 times a day (every 6 to 9 hours)..., we need to be aware that, just at baseline, 40% to 50% of patients...[have] substantial deficits in cognitive functioning."
This investigation established the degree of neurocognitive decline during the first 12 and 48 weeks of treatment. Both HCV-infected and HCV/HIV-coinfected patients were evaluated. Neuropsychological instruments were used to explore which domains of cognitive functioning are most affected by combination pegylated interferon/ribavirin treatment, and whether being coinfected with HIV adds to the decrements in cognitive functioning.
There were no significant differences at baseline between the HCV-infected and HCV/HIV-coinfected cohorts for age, sex distribution, ethnicity, HCV RNA viral load, HCV genotype, or stage of liver disease. There were also no differences between the 2 groups at baseline for neuropsychological scores. However, although the same percentage of patients in the HCV and HCV/HIV cohorts reported depression, HCV patients had significantly worse depression scores.
After treatment, global neuropsychological function declined significantly in HCV patients during the first 24 weeks of HCV treatment. Domains with the greatest declines were memory, executive function, and motor function. "The HCV monoinfected group also had a greater decline in neuropsychological function than the coinfected group in the first 12 weeks," said Dr. Weiss. "This is probably due to more depression among HCV patients at baseline."
How a patient's declining neuropsychological function affects their behavior is key, and can depend on clinical history, Dr. Weiss explained. "Patients who have a history of cognitive dysfunction might respond less to the onset of new symptoms. Patients with a significant pathology who are already well engaged in psychiatric treatment tend to do quite well on [antiretroviral] treatment because they are familiar with the symptoms and are being well managed." Those who are high functioning at baseline will have more trouble; to be successfully managed, the healthcare provider must be aware of the potential for central nervous system (CNS)-related treatment nonadherence.
CNS and the Hepatologist
Raymond T. Chung, MD, vice chief of the gastrointestinal unit and medical director of the liver transplant program at Massachusetts General Hospital in Boston, agrees that the hepatologist must be part psychiatrist. "We field these patients rather then pass them off since there can often be overlap with true advanced hepatic disease and hepatic encephalopathy."
He is mindful of the potential impact of HCV medications. "It has been a modest issue with both HCV/HIV and HCV alone." Symptoms are often called "brain fog," Dr. Chung explained. "This fog does get in the way, in high-functioning individuals, of their ability to carry out intricate calculative functions and memory at work, for instance." It would not be surprising for such a patient to become frustrated and consider forgoing medication, he observed.
Dr. Chung considers the issue manageable if it is proactively addressed. However, like many clinicians at the meeting, he's looking more toward preventing than managing adverse effects by eliminating pegylated interferon from standard HCV treatment.
Dr. Weiss reports being a consultant for Vertex Pharmaceuticals and Kadmon Pharmaceuticals. Dr. Chung has disclosed no relevant financial relationships.
The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting. Abstract 972. November 6, 2011.
Medscape Medical News © 2011 WebMD, LLC
Send comments and news tips to news@medscape.net.
Adverse CNS Effects of HCV Treatment Discourage Adherence
Neil Canavan
November 18, 2011 (San Francisco, California) — Patients infected with hepatitis C virus (HCV) can experience a marked decline in neuropsychological cognitive function in the first 14 weeks of combination pegylated interferon and ribavirin therapy. This poses a potential treat to treatment adherence, said clinical psychologist Jeffrey J. Weiss, PhD, MS, from Mount Sinai School of Medicine in New York City, here at The Liver Meeting 2011: American Association for the Study of Liver Diseases 62nd Annual Meeting.
These data are from a large prospective study looking at early treatment discontinuation and the onset of neuropsychiatric symptomatology in HCV monoinfected and HCV/HIV coinfected treatment-naïve patients receiving combination pegylated interferon/ribavirin therapy, Dr. Weiss explained.
"A lot of work has focused on depression, and not to the decrements in cognitive function," said Dr. Weiss. A host of neuropsychiatric symptoms should be considered when initiating a new treatment.
"In this era of direct-acting antivirals, when we're asking patients to take medications 3 times a day (every 6 to 9 hours)..., we need to be aware that, just at baseline, 40% to 50% of patients...[have] substantial deficits in cognitive functioning."
This investigation established the degree of neurocognitive decline during the first 12 and 48 weeks of treatment. Both HCV-infected and HCV/HIV-coinfected patients were evaluated. Neuropsychological instruments were used to explore which domains of cognitive functioning are most affected by combination pegylated interferon/ribavirin treatment, and whether being coinfected with HIV adds to the decrements in cognitive functioning.
There were no significant differences at baseline between the HCV-infected and HCV/HIV-coinfected cohorts for age, sex distribution, ethnicity, HCV RNA viral load, HCV genotype, or stage of liver disease. There were also no differences between the 2 groups at baseline for neuropsychological scores. However, although the same percentage of patients in the HCV and HCV/HIV cohorts reported depression, HCV patients had significantly worse depression scores.
After treatment, global neuropsychological function declined significantly in HCV patients during the first 24 weeks of HCV treatment. Domains with the greatest declines were memory, executive function, and motor function. "The HCV monoinfected group also had a greater decline in neuropsychological function than the coinfected group in the first 12 weeks," said Dr. Weiss. "This is probably due to more depression among HCV patients at baseline."
How a patient's declining neuropsychological function affects their behavior is key, and can depend on clinical history, Dr. Weiss explained. "Patients who have a history of cognitive dysfunction might respond less to the onset of new symptoms. Patients with a significant pathology who are already well engaged in psychiatric treatment tend to do quite well on [antiretroviral] treatment because they are familiar with the symptoms and are being well managed." Those who are high functioning at baseline will have more trouble; to be successfully managed, the healthcare provider must be aware of the potential for central nervous system (CNS)-related treatment nonadherence.
CNS and the Hepatologist
Raymond T. Chung, MD, vice chief of the gastrointestinal unit and medical director of the liver transplant program at Massachusetts General Hospital in Boston, agrees that the hepatologist must be part psychiatrist. "We field these patients rather then pass them off since there can often be overlap with true advanced hepatic disease and hepatic encephalopathy."
He is mindful of the potential impact of HCV medications. "It has been a modest issue with both HCV/HIV and HCV alone." Symptoms are often called "brain fog," Dr. Chung explained. "This fog does get in the way, in high-functioning individuals, of their ability to carry out intricate calculative functions and memory at work, for instance." It would not be surprising for such a patient to become frustrated and consider forgoing medication, he observed.
Dr. Chung considers the issue manageable if it is proactively addressed. However, like many clinicians at the meeting, he's looking more toward preventing than managing adverse effects by eliminating pegylated interferon from standard HCV treatment.
Dr. Weiss reports being a consultant for Vertex Pharmaceuticals and Kadmon Pharmaceuticals. Dr. Chung has disclosed no relevant financial relationships.
The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting. Abstract 972. November 6, 2011.
Medscape Medical News © 2011 WebMD, LLC
Send comments and news tips to news@medscape.net.
Subscribe to:
Posts (Atom)
Posts
