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2003 Articles

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	Identification of a ribavirin-resistant NS5B mutation of hepatitis C virus during ribavirin monotherapy.
	Anadys Pharmaceuticals Reports Interim Results of Phase 1B Clinical Trial of Isatoribine -ANA245- in Patients Infected with Hepatitis C Virus
	N.Y. Panel OKs New Liver Transplant Rules
	Company in Hepatitis Case Violated Rules
	Drug Maker Recalls Acetaminophen Tablets
	Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis.

	Identification of a ribavirin-resistant NS5B mutation of hepatitis C virus during ribavirin monotherapy. Hepatology. 2003 Oct;38(4):869-78. Young KC, Lindsay KL, Lee KJ, Liu WC, He JW, Milstein SL, Lai MM. Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, 2011 Zonal Avenue, Los Angeles, CA 90089-9094, USA. Ribavirin (RBV), a guanosine analogue, has been suggested to exert an antiviral action against hepatitis C virus (HCV) by causing lethal mutations and suppressing RNA polymerase in vitro, but the mechanism of its clinical therapeutic effects is currently unknown. To test the hypothesis that RBV could act both as an RNA mutagen and inhibit viral RNA synthesis in vivo, we studied the evolution of the nucleotide sequences of HCV RNA at the nonstructural (NS) 5B region in patients receiving RBV, placebo, or interferon alfa (IFN-alpha) monotherapy. The RBV group showed a slightly more accelerated evolution rate of HCV RNA quasispecies than either the IFN-alpha or placebo group. RBV caused preferentially A-to-G and U-to-A mutations. Interestingly, an NS5B amino acid 415 Phe-to-Tyr (F415Y) mutation emerged in all (5 of 5) patients infected with HCV genotype 1a during the RBV treatment. Subsequently, the parental 415F strain reemerged in some patients after the treatment was discontinued. The effect of the amino acid substitution at NS5B415 on HCV RNA replication was then investigated using an HCV subgenomic replicon in Huh7 cells. We showed that treatment of replicon cells with RBV reduced the HCV RNA level of NS5B415F replicon, but not NS5B415Y, in a dose-dependent manner. Thus, NS5B F415Y mutation represents an RBV-resistant variant. The 3-dimensional modeling and structure analysis of NS5B protein revealed that the 415th amino acid is located at the P helix region of the thumb subdomain, which may interact with the minor groove of the template-primer duplex in the putative RNA-binding cleft. In conclusion, RBV could work as a weak mutagen for HCV RNA in HCV-infected patients. Furthermore, the selection of an RBV-resistant variant with a single amino acid substitution in NS5B suggested that RBV may directly interact with HCV RNA polymerase, thus interfering with its enzymatic activity. PMID: 14512874 [PubMed - indexed for MEDLINE]
	Anadys Pharmaceuticals Reports Interim Results of Phase 1B Clinical Trial of Isatoribine -ANA245- in Patients Infected with Hepatitis C Virus Friday December 5, 7:01 am ET Data Presented at the 10th International Meeting on Hepatitis C and Related Viruses Demonstrate Safety and Tolerability and Show Biological Activity SAN DIEGO--(BUSINESS WIRE)--Dec. 5, 2003-- Anadys Pharmaceuticals, Inc. reported today at the 10th International Meeting on Hepatitis C and Related Viruses in Kyoto, Japan that interim results from an ongoing clinical trial of isatoribine (ANA245) demonstrate that the drug is safe and well-tolerated. Although efficacy is not a stated objective of the Phase 1B clinical trial and the number of patients was small, results showed that isatoribine is biologically active in adults with chronic hepatitis C virus (HCV) infection. Isatoribine, which is believed to act by a mechanism of action involving interaction with Toll-like receptor 7 (TLR7) and stimulate the patient's own immune system, is one of a new class of drugs being developed by Anadys to regulate innate immunity, combat hepatitis C virus infection and overcome limitations of current therapies. The data were presented at the meeting by Devron R. Averett, Ph.D., Anadys' Senior Vice President of Drug Development. In an oral presentation at the meeting, Dr. Averett presented data from the first three of four cohorts of an ongoing open-label, dose-escalation Phase 1B clinical trial of isatoribine administered intravenously over a period of seven days to thirteen adults with chronic hepatitis C infection. The trial was designed to determine the safety, tolerability and pharmacokinetics of isatoribine. Results corroborate and extend previously disclosed safety, tolerability, and pharmacokinetic data derived from single doses of isatoribine in healthy volunteers. The study revealed that no serious adverse events were observed with a low frequency of mild to moderate adverse events. The data generated in this clinical trial shows that isatoribine is biologically active in adults with chronic hepatitis C infection based on statistically significant changes in biologic markers; one such biological marker that was measured in the trial was the level of 2'-, 5'-oligoadenylate synthetase (OAS), which increases during interferon-alpha treatment and is thought to mediate antiviral effects. Also, a trend toward reduction of viral load over the seven-day course of treatment was seen. "The interim results of this ongoing Phase 1B trial indicate that isatoribine is well tolerated and biologically active in patients with hepatitis C," said Dr. Averett. "We observed induction of a recognized biological marker for interferon-alpha activity in patients receiving isatoribine, and the magnitude of this induction appears to be dose related." About isatoribine (ANA245) Isatoribine is a patented nucleoside analog Anadys is developing for the treatment of HCV infection. Isatoribine represents one of a new class of drugs being developed by Anadys to regulate innate immunity, combat HCV infection and overcome limitations of current therapies. Anadys believes isatoribine interacts with a specific receptor, Toll-like receptor 7, or TLR7, that is present on certain immune system cells. Although results of initial clinical trials are not necessarily predictive of future results, interim results of the Phase 1B clinical trial show that isatoribine is biologically active in adults with chronic hepatitis C infection and indicate a trend toward reduction of viral load. Anadys expects to initiate a Phase I/II clinical trial of isatoribine in HCV patients in the beginning of 2004. About hepatitis C Hepatitis C virus causes inflammation of the liver and degradation of liver function. Hepatitis C infection is currently the most common chronic blood-borne infection in the United States. Approximately 2.7 million people in the United States are chronically infected with the hepatitis C virus, and it causes 10,000 to 12,000 deaths a year in the United States. The Centers for Disease Control and Prevention, or CDC, estimates the annual mortality rate in the United States could increase to 38,000 by the year 2010, surpassing the number of deaths attributed annually to HIV/AIDS. The hepatitis C virus is transmitted primarily through significant or repeated exposures to infected blood. In the United States, intravenous drug use and sexual contact with infected persons account for the majority of new hepatitis C infections. Approximately two thirds of new infections progress to chronic infection. Chronic HCV infection may also progress to more serious complications such as cirrhosis of the liver, liver cancer and death. Anadys Pharmaceuticals, Inc. (www.anadyspharma.com) is a biopharmaceutical company committed to advancing patient care by discovering, developing and commercializing novel and powerful small molecule, anti-infective medicines for the treatment of hepatitis C virus, or HCV, and bacterial infections. Anadys integrates biology and chemistry into a seamless, feedback-based, iterative process to facilitate rapid and successful drug discovery. The approach is designed to advance a strong and continual pipeline of drug candidates into the clinic. For more information, please visit www.anadyspharma.com. Statements in this press release that are not strictly historical in nature constitute "forward-looking statements." Such statements include, but are not limited to, references to the biological activity of isatoribine in HCV infected patients, the trend toward viral load reduction resulting from administration of isatoribine in those patients, the believed mechanism of action of isatoribine and its effect on a patient's immune system, and expectations regarding further clinical trials of isatoribine. Such forward-looking statements involve known and unknown risks, uncertainties and other factors, which may cause the actual results of Anadys Pharmaceuticals to be materially different from historical results or from any results expressed or implied by such forward-looking statements. In particular, the results of initial clinical trials are not necessarily predictive of future results, and Anadys can provide no assurances that isatoribine will have favorable results in later clinical trials, or receive regulatory approval. This and other factors that may cause actual results to differ are more fully discussed in the "Risk Factors" section of Anadys' Registration Statement on Form S-1 on file with the SEC. Anadys is providing this information as of this date and does not undertake any obligation to update any forward-looking statements contained in this document as a result of new information, future events or otherwise. -------------------------------------------------------------------------------- Contact: Anadys Pharmaceuticals, Inc., San Diego Michael Kamdar, 858-530-3667 cc@anadyspharma.com or Atkins & Associates Liz Thompson, 858-527-3492 lthompson@irpr.com -------------------------------------------------------------------------------- Source: Anadys Pharmaceuticals, Inc.
	N.Y. Panel OKs New Liver Transplant Rules Dec 4, 3:29 PM (ET) By ALICIA CHANG ALBANY, N.Y. (AP) - A state council endorsed new rules to make liver transplants safer by creating an independent donor advocate team, but stopped short of giving the team the power to override a donor's wishes. The state Hospital Review and Planning Council approved the revised rules without discussion Thursday. The regulations now go to Health Commissioner Antonia Novello, who had pushed for reform after a 57-year-old man died donating part of his liver to his brother almost two years ago. Under the rules, a prospective live donor would be assigned a donor advocate team made up of a doctor, transplant coordinator, social worker and psychiatrist. The team would evaluate whether the donor is medically and psychologically suitable for an operation, but would not have actual veto power. If the advocates object to a liver donation, their opposition would be noted in a report to the surgeon, who has the final say and who would have to give reasons for continuing against the advocates' advice. Last December, the State Transplant Council endorsed rules allowing advocates to deny the right to donate. But health experts raised concerns about a third party interfering with the decision-making process between a doctor and patient. In September, the Health Department published a notice modifying the transplant rules. After a public comment period that ended Nov. 8, the state Hospital Review and Planning Council reviewed the issue. Before the council voted Thursday, Dennis Whalen, executive deputy health commissioner, said New York should be proud of its "pioneering work" to protect donors and recipients. Michael Hurewitz, a reporter for the Times Union of Albany, died Jan. 13, 2002, at Mount Sinai Hospital, three days after donating 60 percent of his liver to his brother. A state board found Hurewitz received inadequate post-surgical care. His brother survived. The new rules eliminate setting a donor age limit of 55, allowing hospitals to decide on a case-by-base basis. The rules also mandate minimum staffing levels at hospitals that perform live liver transplants including one nurse for every two patients in intensive care and post-anesthesia units and one nurse for every four patients transferred to other units. Five hospitals in New York state transplant livers, including Westchester Medical Center, New York Presbyterian Hospital, New York University Hospital, Strong Memorial Hospital and Mount Sinai. The five hospitals said they are already in substantial compliance. Transplant centers also will have to collect and report information to the Health Department about donors during the donation process and afterward. The data will help doctors and potential donors learn about any long-term risks of live liver donation.
	Company in Hepatitis Case Violated Rules Dec 5, 7:01 PM (ET) By OLGA R. RODRIGUEZ MONTERREY, Mexico (AP) - U.S. inspectors visiting green-onion producers in northwestern Mexico found that one of the four companies linked to a deadly U.S. hepatitis outbreak failed to meet hygiene standards, Mexican officials said Friday. Javier Trujillo, undersecretary for food safety and quality in Mexico's Ministry of Agriculture, said Dos M Sales de Mexico, a company located near the border city of Mexicali, in Baja California state, was washing its scallions with water from a nearby reservoir, rather than with purified drinking water, as required. "The deficiencies where found at the company's packing operation but that is not conclusive proof that this was the origin of the hepatitis outbreak in the United States," Trujillo said. The other three companies linked to the outbreak that killed three people and sickened more than 600 in Pennsylvania are Agricola La Laguna, a.k.a. Sun Fresh, of Ensenada; Tecnoagro International in San Luis Rio Colorado and Ensenada, and Agro Industrias Vigor in Tijuana, Ojos Negros and San Quintin, Baja California. The probe by three inspectors from the U.S. Food and Drug Administration and one from U.S. Centers for Disease Control and Prevention - accompanied by Mexican officials - started Monday, and will continue next week when inspectors will visit scallion-exporting companies not linked to the hepatitis A outbreak, Trujillo said. But Trujillo said the FDA rushed to judgment by publicly identifying suspected companies before completing an investigation that followed the green-onions through the supply chain. "The hypothesis that the outbreak could have originated in Mexico is one, but there is also the likelihood of contamination in the transportation, or at the restaurant," Trujillo said. "It's really surprising that the FDA would only emphasize the hypothesis of contamination at the point of origin." Ellen Morrison, director of the Office of Crisis Management for the FDA, said the FDA has been very careful with the investigation and sent the inspection team to Mexico only after not finding sources of contamination at the different restaurants. She said it's premature to speak of the inspectors' findings while the investigation is in progress. The hepatitis strains found in the rash of illnesses among customers at a Chi-Chi's restaurant at the Beaver Valley Mall northwest of Pittsburgh are very similar to those found in smaller outbreaks that occurred in Tennessee and Georgia in September. Those earlier outbreaks were traced to three companies known to have supplied Mexican green onions in those states. It is unclear whether they are the same companies currently being investigated.
	Drug Maker Recalls Acetaminophen Tablets Email this Story Dec 5, 1:16 PM (ET) WASHINGTON (AP) - An Oregon drug maker is recalling one lot of painkiller because the tablets contain more of the drug than shown on the label. The recall covers 504 bottles of Dixon's APAP Acetaminophen tablets labeled 325 milligrams. The tablets contained in the bottle, however, contained 500 milligrams of the drug. The 100-tablet bottles were sold nationwide beginning in August. The manufacturer, Magno-Humphries, Inc., of Tigard, Ore., said the recalled product carry lot number 319867 and the expiration date 03/05. Overdoses of acetaminophen can lead to severe health problems including liver failure, but the company said Friday no adverse effects have been reported. Buyers of the pills were urged to stop using them immediately and return them to the place of purchase for a refund. Those needing more information can call 1-800-935-6737. 5: Am J Gastroenterol. 2003 Nov;98(11):2485-90. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Harrison SA, Torgerson S, Hayashi P, Ward J, Schenker S. Brooke Army Medical Center, University of Texas Health Science Center San Antonio, San Antonio, Texas, USA Nonalcoholic steatohepatitis (NASH) is a common cause of liver disease. Although usually indolent, this disease can progress to cirrhosis in some patients. There is currently no proven medical therapy for the treatment of NASH. The aim of our study was to evaluate the efficacy of combination alpha-tocopherol (vitamin E) and vitamin C in reducing histologic inflammation and fibrosis.This was a prospective, double-blind, randomized, placebo-controlled trial with a total enrollment of 49 patients; 45 patients completed the study. All patients were randomized to receive either vitamins E and C (1000 IU and 1000 mg, respectively) or placebo daily for 6 months, based on their initial histologic diagnosis of NASH. Additionally, all patients were given standard weight-loss counseling and encouraged to follow a low fat diet (<30 fat g/day). The pre- and posttreatment liver biopsies were reviewed by a single pathologist, who was blinded to the patient's medication. Biopsies were scored based on a modification of the scoring system published by Brunt et al. (Am J Gastroenterol 1999;94:2467-74). A score of 0-4 was possible for fibrosis, and a score of 0-6 was possible for inflammation and hepatocyte degeneration and necrosis. In addition, body mass index, glycohemoglobin, lipids, and liver enzymes were followed throughout the study.Forty-five patients completed 6 months of therapy without significant side effects. Vitamin treatment resulted in a statistically significant improvement in fibrosis score (p = 0.002). No changes were noted in inflammation with treatment.Vitamin E and vitamin C, in the doses used in this study, were well tolerated and were effective in improving fibrosis scores in NASH patients. No improvement in necroinflammatory activity or ALT was seen with this combination of drug therapy. A larger, multicenter, longer-term trial with vitamin E and vitamin C seems to be warranted. PMID: 14638353 [PubMed - in process]