ZALBIN is a long-acting investigational treatment for chronic hepatitis C, and is being developed by HGS and Novartis under an exclusive worldwide co-development and commercialization agreement entered into in June 2006 [1-2]. ZALBIN has successfully completed Phase 3 development in chronic hepatitis C, and we expect the submission of global marketing applications in fall 2009. Phase 3 trial results showed that, with half the injections, ZALBIN achieved efficacy comparable to Pegasys (peginterferon alfa-2a) with a positive safety profile [3-7]. Assuming licensure by the FDA and other regulatory agencies, HGS believes that ZALBIN could become a market-leading treatment for chronic hepatitis C.

How ZALBIN Works

ZALBIN appears to induce a biological effect similar to that induced by currently available recombinant interferon alfa treatments. Microarray gene expression data show that ZALBIN up-regulates, or increases the activity of, the same 31 genes that recombinant interferon alfa up-regulates in a dose-dependent manner [8-9]. The interferons belong to a family of proteins known as cytokines that occur naturally in the human body. Cytokines control cellular processes, such as cell growth, activation, migration and aging.

While the precise mechanism of action of interferon alfa is not fully understood, research has demonstrated that interferon alfa has direct antiviral activity in patients with diseases such as hepatitis C, as well as immune-modulating and direct antitumor effects in certain types of cancer [10-12].

HGS has successfully completed two Phase 3 clinical trials of ZALBIN: ACHIEVE 1, which was conducted in patients with genotype 1 chronic hepatitis C, and ACHIEVE 2/3, which was conducted in patients with genotypes 2 and 3 chronic hepatitis C. The results of both studies were reported in April 2009 at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL) [3-5]. The data presented at EASL demonstrate that, with half as many injections, in two pivotal Phase 3 trials, ZALBIN (albinterferon alfa-2b) met its primary efficacy endpoint by achieving a rate of sustained virologic response comparable to Pegasys (peginterferon alfa-2a). The rates of serious and/or severe adverse events were also comparable in both studies.

Molecular Model of ZALBIN


Figure 1. ZALBIN is a single polypeptide molecule that combines the therapeutic activity of interferon alfa with the long half-life of human serum albumin.

Collaboration with Novartis for Development and Commercialization of ZALBIN

In June 2006, HGS entered into an exclusive worldwide agreement with Novartis for the co-development and commercialization of ZALBIN [1-2]. Novartis is a global leader in the pharmaceutical industry and has demonstrated its commitment to leadership in infectious diseases. HGS and Novartis are working closely together to advance ZALBIN to the market.

Under the agreement, HGS and Novartis will co-commercialize ZALBIN in the United States, and will share clinical development costs, U.S. commercialization costs and U.S. profits equally. Novartis will be responsible for commercialization in the rest of the world and will pay HGS a royalty on those sales. The brand name selected for albinterferon alfa-2b in the rest of the world is JOULFERON®. HGS will have primary responsibility for the bulk manufacture of ZALBIN, and Novartis will have responsibility for commercial manufacturing of the finished drug product. Clinical development, commercial milestone and other payments to HGS could total as much as $507.5 million, including $132.5 million received to date and a $75 million payment expected in fourth quarter 2009.

Potential Treatment Settings

HGS and Novartis are currently developing ZALBIN as a potential treatment for chronic hepatitis C. Hepatitis C is an inflammation of the liver caused by the hepatitis C virus. It is the most common chronic blood-borne infection in the developed world [10]. It is estimated that approximately 170 million people worldwide are infected with the hepatitis C virus, including approximately four million people in the United States. The hepatitis C virus can cause serious liver disease, leading to cirrhosis, primary liver cancer and even death.

When detectable levels of the virus persist in the blood for at least six months, a person is diagnosed as having chronic hepatitis C. Between 60% and 85% of people infected with hepatitis C develop chronic hepatitis C. The current standard of care is a combination of pegylated interferon alfa and ribavirin, an antiviral drug [11-13].

ZALBIN Pharmacokinetics


Figure 2. Results of a Phase 2 study of ZALBIN in treatment-naïve patients demonstrate that ZALBIN was detectable in the blood for up to four weeks following the second subcutaneous injection.

Phase 3 Results

In April 2009, HGS reported that ZALBIN (albinterferon alfa-2b), in both of its two pivotal Phase 3 trials, met its primary endpoint of non-inferiority to peginterferon alfa-2a (Pegasys) in the treatment of chronic hepatitis C. The Phase 3 results were presented in Copenhagen at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL) [3-5]. The data presented at EASL demonstrate that ZALBIN, with half as many injections, achieved a rate of sustained virologic response (SVR) comparable to peginterferon alfa-2a. The rates of serious and/or severe adverse events were also comparable in both studies.

Phase 3 Efficacy Finding

Based on an intention-to-treat (ITT) analysis, the data presented at EASL demonstrate that ZALBIN (albinterferon alfa-2b) met its primary efficacy endpoint of non-inferiority to peginterferon alfa-2a in both ACHIEVE 1 and ACHIEVE 2/3:

ACHIEVE 1: 48.2% (213/442) of patients in the 900-mcg albinterferon alfa-2b treatment group achieved sustained virologic response (SVR), vs. 51.0% (225/441) in the peginterferon alfa-2a treatment group. The primary analysis, which was adjusted for baseline stratification factors, showed a difference in SVR rates of -1.8% (95% CI -8.1%, 4.5%, p=0.0008 for non-inferiority).
ACHIEVE 2/3: 79.8% (249/312) of patients achieved SVR in the 900-mcg albinterferon alfa-2b treatment group, vs. 84.8% (263/310) in the peginterferon alfa-2a group (p=0.0086 for non-inferiority). The primary analysis, which was adjusted for baseline stratification factors, showed a difference in SVR rates of -4.8% (95% CI -10.7%, 1.1%, p=0.0086 for non-inferiority).
- An unexpectedly high and still unexplained SVR rate for peginterferon alfa-2a in the Asian region fully accounted for the observed SVR difference between the two drugs in the ACHIEVE 2/3 study.
- In non-Asian regions, 79.8% (174/218) of patients achieved SVR in the 900-mcg albinterferon alfa-2b treatment group, vs. 80.5% (178/221) in the peginterferon alfa-2a group. In Asia, 79.8% (75/94) of patients achieved SVR in the 900-mcg albinterferon alfa-2b treatment group, vs. 95.5% (85/89) in the peginterferon alfa-2a group.

Phase 3 Safety Findings

Across the two albinterferon alfa-2b Phase 3 trials, rates of serious and/or severe adverse events were comparable in all dose groups, including 21.2% (160/755) for 900-mcg albinterferon alfa-2b, and 20.8% (156/750) for 180-mcg peginterferon alfa-2a.

The incidence of fatality in the albinterferon alfa-2b Phase 3 trials was rare. All-cause mortality rates were 0.13% (1/755) for 900-mcg albinterferon alfa-2b every two weeks, and 0.27% (2/750) for 180-mcg peginterferon alfa-2a.

Rates of discontinuation due to adverse events across the two studies were 8.1% (61/755) for 900-mcg albinterferon alfa-2b, vs. 3.9% (29/750) for peginterferon alfa-2a. The causes of discontinuation for both drugs were those typical for interferon-based therapy.

Overall, adverse events observed were those typically associated with interferon therapy, and most were similar for 900-mcg albinterferon alfa-2b and peginterferon alfa-2a.

About the Phase 3 Clinical Development Program

The ZALBIN Phase 3 clinical development program included two randomized, open-label, active-controlled, multi-center, non-inferiority trials to evaluate the efficacy and safety of ZALBIN in combination with ribavirin, versus Pegasys (peginterferon alfa-2a) in combination with ribavirin [14-17]. HGS designed the Phase 3 program for ZALBIN in collaboration with Novartis and leading international experts in hepatitis C. The Company also reviewed the trial designs with U.S. and key European regulatory authorities and received their positive feedback.

ACHIEVE 1 enrolled a total of 1331 patients with genotype 1 chronic hepatitis C at 149 clinical sites in 12 countries in North America, Europe and elsewhere. Patients were initially randomized into three treatment groups, including two groups receiving subcutaneously administered ZALBIN once every two weeks (900 mcg or 1200 mcg), and an active control group receiving Pegasys once every week at the standard dose of 180 mcg. All patients received daily oral ribavirin concomitantly. The total duration of therapy in ACHIEVE 1 was 48 weeks, which is standard for genotype 1 patients, with 24 weeks of follow-up. The primary efficacy endpoint is sustained virologic response (SVR), defined as undetectable HCV RNA (< 10 IU/mL) at Week 72.

ACHIEVE 2/3 enrolled a total of 933 patients with genotypes 2 and 3 chronic hepatitis C at 136 sites in 19 countries in North America, Europe, Latin America and Asia. Patients were initially randomized into three treatment groups, which received the same doses of ZALBIN and Pegasys administered on the same schedules as ACHIEVE 1, with concomitant daily administration of oral ribavirin. The total duration of therapy in ACHIEVE 2/3 was 24 weeks, with 24 weeks of follow-up. The primary efficacy endpoint was SVR, defined as undetectable HCV RNA at Week 48.

In January 2008, a dose modification was made for patients in both trials who were originally assigned to receive the 1200-mcg dose of ZALBIN [15]. Patients who had been receiving the 1200-mcg ZALBIN dose had their dose modified to 900 mcg. The 900-mcg dose group was not affected by this change.

How ZALBIN Was Created

ZALBIN (also known as JOULFERON®) is a genetic fusion of human albumin and interferon alfa. Human albumin is the most prevalent naturally occurring blood protein in the human circulatory system, persisting in circulation in the body for approximately 19 days. Research has shown that genetic fusion of therapeutic proteins to albumin decreases clearance and prolongs the half-life of the therapeutic proteins. [19-20]

The proprietary HGS albumin-fusion technology allows scientists to create next-generation protein drugs by fusing the gene that expresses human albumin to the gene that expresses a therapeutically active protein. ZALBIN results from the genetic fusion of human albumin and interferon alfa.

For More Information about ZALBIN Clinical Trials

Health professionals and patients interested in ZALBIN (albinterferon alfa-2b) clinical trials or other studies involving HGS products may inquire via email to This e-mail address is being protected from spam bots, you need JavaScript enabled to view it or by calling HGS at (877) 822-8472. Information about HGS clinical trials may also be found at www.clinicaltrials.gov.

Footnotes

(HGSI Press Release) Human Genome Sciences Announces Collaboration with Novartis for Development and Commercialization of Albuferon. June 6, 2006.
(Novartis Press Release) Novartis Strengthens Infectious Diseases Portfolio by Acquiring Rights to Albuferon, a Novel Hepatitis C Interferon Compound Set to Enter Phase III Trials. June 6, 2006.
(HGSI Press Release) Human Genome Sciences Reports Positive Late-Breaker Results at EASL from ACHIEVE Phase 3 Trials of Albuferon in Patients with Chronic Hepatitis C. April 25, 2009.
Zeuzem S, Sulkowski M, Lawitz E, McHutchison J, et al. Efficacy and safety of albinterferon alfa-2b in combination with ribavirin in treatment-naïve patients with chronic hepatitis C genotype 1. Oral presentation. 44th Annual Meeting of the European Association for the Study of the Liver. April 25, 2009.
Nelson D, Benhamou Y, Chuang WL, McHutchison J, et al. Efficacy and safety results of albinterferon alfa-2b in combination with ribavirin in treatment-naïve patients with chronic hepatitis C genotype 2 or 3. Oral presentation. 44th Annual Meeting of the European Association for the Study of the Liver. April 25, 2009.
(HGSI Press Release) Human Genome Sciences Announces Positive Results in Second of Two Phase 3 Trials of Albuferon in Chronic Hepatitis C. March 9, 2009.
(HGSI Press Release) Human Genome Sciences Announces Albuferon Meets Primary Endpoint in Phase 3 Trial in Chronic Hepatitis C. December 8, 2008.
Moore P, Balan V, et al. Modulation of interferon specific gene expression by Albuferon in subjects with chronic hepatitis C and correlation with anti-viral response. 40th Annual Meeting of the European Association for the Study of the Liver. April 14, 2005. (Abstract #447).
Balan V, et al. Molecular profiles of drug response in HCV infected patients during the first four weeks of therapy for chronic hepatitis C virus with pegylated interferon containing regimens or Albuferon. 54th Annual Meeting of the American Association for the Study of Liver Diseases. October 25, 2003.
Alter MJ. Epidemiology of hepatitis C in the West. Semin Liver Dis 1995; 15:5-14.
Strader DB, Wright T, Thomas DL, and Seeff LB. AASLD practice guideline: diagnosis, management, and treatment of hepatitis C. Hepatology 2004 April; 39 (4): 1147-1171.
Perry CM, Jarvis B, et al. Peginterferon-alpha-2a (40 kD): a review of its use in the management of chronic hepatitis C. Drugs 2001; 61:2263-2288.
Glue P, Fang JWS, Rouzier-Panis R, et al. Pegylated interferon-alpha 2b: pharmacokinetics, pharmacodynamics, safety and preliminary efficacy data. Clinical Pharm Ther 2000; 68:556-567.
(HGSI Press Release) Human Genome Sciences Completes Enrollment Ahead of Schedule in Second Phase 3 Albuferon Trial. November 1, 2007.
(HGSI Press Release) Human Genome Sciences Completes Patient Enrollment in Phase 3 Albuferon Trial Ahead of Schedule. August 28, 2007.
(HGSI Press Release) Human genome Sciences Initiates Pivotal Phase 3 Clinical Trials of Albuferon. December 19, 2006.
(HGSI Press Release) Human Genome Sciences Announces Phase 3 Clinical Development Program for Albuferon™ in Chronic Hepatitis C. October 4, 2006.
(HGSI Press Release) Human Genome Sciences Modifies Dosing in ACHIEVE Trials of Albuferon. January 23, 2008.
Subramanian GM, McHutchison JG, Zeuzem S, et al. Albinterferon alfa-2b: a genetic fusion protein for the treatment of chronic hepatitis C. Nature Biotechnology. December 2007.
Peters T. All about albumin. Academic Press, San Diego, CA. 1996.

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To view announcements on Albuferon, click on the following:

Human Genome Sciences Announces $75 Million Milestone Payment for ZALBIN™ Progress - October 19, 2009

Human Genome Sciences Announces Completion of Enrollment in Phase 2b Monthly-Dosing Trial of Albuferon® - June 19, 2009

Human Genome Sciences Reports Positive Late-Breaker Results at EASL from ACHIEVE Phase 3 Trials of Albuferon in Patients with Chronic Hepatitis C - April 25, 2009

Human Genome Sciences Announces Positive Results In Second Of Two Phase 3 Trials Of Albuferon® In Chronic Hepatitis C - March 9, 2009

Human Genome Sciences Announces Initiation of Phase 2b Trial of Albuferon® Dosed Monthly in Chronic Hepatitis C - January 12, 2009

Human Genome Sciences Announces Albuferon Meets Primary Endpoint in Phase 3 Trial in Chronic Hepatitis C - December 8, 2008

Human Genome Sciences Modifies Dosing in ACHIEVE Trials of Albuferon - January 23, 2008

Human Genome Sciences Presents Results of Phase 2 Trial of Albuferon® in Chronic Hepatitis C Patients who Failed to Respond to Previous Therapy - November 5, 2007

Human Genome Sciences Announces Full Presentation of Quality-of-Life Results from Phase 2b Trial of Albuferon® for Hepatitis C - November 5, 2007