Human Genome Sciences, Inc. announced that interim results from an ongoing clinical trial of Albuferon demonstrate that the drug is well tolerated, has a prolonged half-life, and is biologically active in treatment-experienced adults with chronic hepatitis C. Data from ongoing clinical and observational studies were presented at the 54th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), which concluded on October 28 in Boston, MA. Albuferon is Human Genome Sciences' long-acting form of recombinant interferon alpha.
A poster entitled A Phase 1/2 Study to Evaluate the Pharmacokinetics, Safety, Tolerability, Immunogenicity, and Pharmacodynamics of Albuferon in Treatment Experienced Subjects with Chronic Hepatitis C (Abstract #1352) presented data on sixty-nine patients treated in an ongoing multi-center, open-label, dose-escalation study. The Phase 1/2 clinical trial is designed to determine the safety and pharmacology of Albuferon in adults with chronic hepatitis C who have failed previous interferon alpha treatments.
Ninety-five per cent (66 of 69) of the patients participating in the trial were infected with hepatitis C virus (HCV) genotype 1, which accounts for nearly seventy percent of all HCV infections in the United States and is generally regarded as the most difficult HCV genotype to treat. Patients participating in the study had been treated for an average of 68 weeks with interferon alpha or pegylated interferon alpha, either alone or in combination with ribavirin, prior to entering the Albuferon study.
Safety and tolerability data were presented on all treated patients. Biological activity data were presented on twenty-eight patients who were enrolled under an amendment to the original protocol and were treated with single doses of Albuferon administered subcutaneously at 120 mcg, 180 mcg, 240 mcg, 320 mcg, or 400 mcg. Seventy-five per cent (21 of 28) of the subjects treated in these cohorts had been treated previously with pegylated interferon alpha. Additional fourteen-day safety and antiviral response data were presented for six subjects who received single 500 mcg doses of Albuferon. The primary purpose of the ongoing trial is to determine Albuferon's safety, tolerability, immunogenicity, and pharmacokinetics. Pharmacodynamics and biological activity also are being evaluated.
Interim results show that Albuferon is well tolerated, has a prolonged half-life, and is biologically active in adults with chronic hepatitis C. No patient has developed a detectable anti-Albuferon immune response. As expected based on clinical and preclinical results previously reported, Albuferon remains in the blood substantially longer than is reported for recombinant interferon alpha and pegylated interferon alpha. Albuferon exhibits a median half-life of 145 hours at doses of 80 mcg or higher. This compares to a reported mean elimination half-life of 80 hours (50-140 hours) for Pegasys and 40 hours (22-60 hours) for PEG-Intron.
All dose cohorts treated under the amended protocol showed evidence of biological activity. 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 was found to be capable of inducing prolonged elevations of 2', 5' OAS mRNA. The elevations in 2', 5' OAS mRNA were sustained for up to twenty-eight days following a single injection of Albuferon.
Viral load levels represent the quantity of hepatitis C virus in the blood and are a surrogate marker for clinical benefit. Fifty-seven percent (16/28) of Albuferon-treated patients experienced an antiviral response following a single dose, as demonstrated by reductions in their viral load of 0.5 log or greater, with the majority of those patients (13/16) experiencing reductions of 0.9 log or greater. Statistically significant (p-value < .05) reductions in viral load were observed at days 2-14 in all patients who received a single 500 mcg injection of Albuferon. In addition, levels of alanine aminotransferase (ALT), which are elevated by liver cell injury, were reduced substantially in twenty-nine percent of the Albuferon-treated patients with elevated baseline levels.
Vijayan Balan, M.D., a lead investigator and Director, Hepatobiliary Clinic, Division of Transplant Medicine and Division of Gastroenterology and Hepatology, Mayo Clinic Hospital, Phoenix, AZ, said, "The available therapies for patients with chronic hepatitis C frequently are associated with side effects that often require dose adjustments and can require discontinuation of treatment. There is a significant need to provide these patients with treatment options that are more convenient and hopefully have fewer side effects. Currently, patients are treated with alpha interferon three times weekly, or with pegylated interferon once weekly, along with daily doses of ribavirin. The pharmacokinetic behavior of Albuferon suggests a potential for dosing at intervals of from two to four weeks. These interim clinical results are encouraging, particularly considering that Albuferon has been administered as a single injection only at the higher doses and a maximum tolerated dose has not yet been reached. We look forward to continuing to evaluate Albuferon as a potential treatment for chronic hepatitis C."
Human Genome Sciences presented the results of the original trial protocol at the 2002 AASLD meeting. Results showed that Albuferon administered in either single doses subcutaneously, or two doses subcutaneously fourteen days apart, at 7 mcg, 20 mcg, 40 mcg, or 80 mcg is well tolerated and biologically active. Human Genome Sciences amended the Phase 1 clinical trial protocol to continue the evaluation of Albuferon's safety, tolerability, and pharmacology in single-dose and two-dose cohorts at higher doses to seek the maximum biological response that can be achieved at a tolerable dose. Under the amended protocol, Human Genome Sciences is currently continuing to dose-escalate up to doses of 600 mcg, and to evaluate two injections administered fourteen days apart at multiple dose levels. The trial is expected to conclude during the first half of 2004. Further Phase 2 studies are planned.
A poster entitled Molecular Profiles of Drug Response in HCV Infected Patients During the First 4 Weeks of Therapy for Chronic Hepatitis C Virus with Pegylated Interferon Containing Regimens or Albuferon (Abstract # 328) described the preliminary results of an observational study designed to define the gene expression profiles of Albuferon and standard-of-care treatments that include pegylated interferon alpha.2 Blood was obtained from 18 HCV-infected patients (12 interferon-naive and 6 interferon-experienced) on days 0, 7 and 28 after standard-of-care therapy was initiated. cDNA was synthesized from extracted RNA and hybridized to high-density microarray membranes. Hierarchical cluster analysis was used to determine the degree of similarity between expression profiles.
The preliminary observational study data confirm the previously reported pharmacodynamics (reductions in HCV viral load and in ALT levels) and pharmacokinetics of pegylated interferon alpha/ribavirin combination therapy during the first four weeks of treatment.
The data further demonstrate that: (1) OAS mRNA induction on days 7 and 28 is comparable for a single injection of Albuferon and standard-of-care regimens containing pegylated interferon alpha; and (2) cDNA array analysis at day 7 shows a molecular profile consistent with drug response for both a single dose of Albuferon and standard-of-care regimens containing pegylated interferons. Future analyses are planned to determine whether gene expression patterns are predictive and/or correlative of clinical response as measured by HCV viral load and ALT reduction.
David Nelson, M.D., a lead author and clinical trial investigator, Chief, Section of Hepatobiliary Diseases, and Medical Director, Liver Transplantation, University of Florida, Gainesville, FL, said, "Data from this observational study provide insight for the first time into how interferon works at the molecular level in patients undergoing therapy. Preliminary results from the cDNA array analysis show that Albuferon and treatment regimens containing pegylated interferon produce molecular signatures consistent with drug response. Preliminary data further demonstrate that, within the first seven days of treatment, the molecular signatures are comparable across therapy groups. In future analyses, we hope to apply this pharmacogenomic approach to elucidate molecular surrogate markers for clinical outcomes and toxicity."
David C. Stump, M.D., Senior Vice President, Drug Development, said, "The interim results of our ongoing Phase 1/2 study demonstrate that a single injection of Albuferon at the higher doses tested under our amended protocol is well tolerated, clearly active, and capable of inducing reductions in HCV viral load in the majority of patients. It is worth noting that in most of the patients who experienced a reduction in viral load in the higher dose cohorts, a reduction of 0.9 log or greater was observed. Elevations in the mRNA of a recognized biological marker for interferon-alpha activity, 2', 5'-oligoadenylate synthetase, continue to be observed, and were sustained in these patients for up to twenty-eight days following a single injection of Albuferon. In addition, substantial reductions in blood levels of alanine aminotransferase, an indicator of liver cell injury, were seen in twenty-nine percent of the patients with elevated baseline levels who were treated with Albuferon. Based on the clinical and observational study results to date, we will continue to evaluate Albuferon at higher doses and in repeated doses to obtain additional safety and biological activity data and to identify the optimal starting dose for future studies. We also plan to evaluate Albuferon in additional Phase 2 studies.
"We are encouraged by the preliminary results of the observational study, which show that, at the molecular level, Albuferon behaves in a similar manner to treatment regimens containing pegylated interferon alpha. We look forward to the results of future analyses to understand whether gene expression patterns can be predictive of clinical benefit."
Craig A. Rosen, Ph.D., President, Research and Development, said, "Hepatitis C is a major public health problem in the United States and throughout the world. In the United States alone, nearly four million people are infected with the hepatitis C virus. The results reported today reinforce our belief that Albuferon has the potential to provide these patients with a new long-acting treatment option, with a considerably more convenient treatment schedule, and perhaps with improved efficacy or safety."
Albuferon is a novel, long-acting form of interferon alpha. Recombinant interferon alpha is approved for the treatment of hepatitis C, hepatitis B, and a broad range of cancers. Human Genome Sciences modified interferon alpha to improve its pharmacological properties by using the company's proprietary albumin fusion technology. Albumin fusion technology allows scientists to create novel, next-generation protein drugs by fusing the gene that expresses human albumin to the gene that expresses a therapeutically active protein. Albuferon results from the genetic fusion of human albumin and interferon alpha. Human Genome Sciences is developing Albuferon for use in the treatment of chronic hepatitis C.
Hepatitis C infection is an inflammation of the liver caused by the hepatitis C virus. Hepatitis C infection is currently the most common chronic blood-borne infection in the United States, afflicting four times as many people as are infected with HIV, the virus that causes 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. When detectable levels of the hepatitis C virus in the blood persist for at least six months, a person is diagnosed as having chronic hepatitis C. Approximately four million people in the United States are infected with the hepatitis C virus, and between sixty and eighty-five percent of hepatitis C-infected people develop chronic hepatitis C. A four-fold increase in the number of adults diagnosed with chronic hepatitis C is projected from 1990 to 2015.