DDW Article Title

94% of Hepatitis B Patients Receiving Entecavir Experience Undetectable HBV Viral Load Compared to 77% of Patients Receiving Lamivudine

Entecavir (Baraclude) is a nucleoside analogue approved for marketing in the U S by the U.S. Food and Drug Administration (FDA) on March 29, 2005. Entecavir is indicated for the treatment of chronic hepatitis B virus infection in adults with evidence of active hepatitis B viral replication with either evidence of serum aminotransferases (ALT or AST) or histologically active disease.

According to presentations of two Phase III studies at the Digestive Disease Week 2006 (DDW 2006) conference in Los Angeles (May 20-25, 2006),
after up to 96-weeks of treatment, 94 percent of nucleoside-naïve HBeAg-negative chronic hepatitis B patients treated with entecavir experienced an undetectable hepatitis B viral load (<300 copies/mL) compared to 77 percent of patients treated with lamivudine (Epivir-HBV).

In addition, no evidence of entecavir resistance was identified in these patients.
Additional 96-week study data presented by Bristol-Myers Squibb evaluated the use of entecavir compared to continued lamivudine in lamivudine-refractory, HBeAg-positive chronic hepatitis B patients.

After up to 96-weeks of treatment, 30 percent of patients who were switched to entecavir treatment achieved an undetectable viral load, compared to less than 1 percent of patients who continued lamivudine treatment (p< 0.0001, based on cumulative analysis of all treated patients). Viral rebound due to entecavir resistance occurred in 9 percent of patients through Week 96 and required the prior presence of LVD-resistance substitutions.

“It is increasingly recognized that hepatitis B viral load is an important evaluation tool for physicians when assessing, monitoring, and managing patients,” said Morris Sherman, M.D., an entecavir study investigator and associate professor of medicine at the University of Toronto.

Study ETV-027 was a large-scale, multinational, Phase III clinical trial of 638 HBeAg-negative chronic hepatitis B patients who had not previously received nucleoside treatment. In the study, patients received either entecavir 0.5 mg once daily (n=325) or lamivudine 100 mg once daily (n=313) for a minimum of 52 weeks.

At Week 52, patients were categorized into one of three groups based on evaluations at Week 48: non-responders (HBV DNA by branched DNA (bDNA) ≥0.7 MEq/mL) who discontinued treatment; responders (HBV DNA by bDNA <0.7 MEq/mL and alanine aminotransferase (ALT) <1.25 times the upper limit of normal) who discontinued treatment and were followed for 24 weeks off-treatment; and virologic responders (HBV DNA by bDNA <0.7 MEq/mL and ALT ≥1.25 x ULN) who went on to receive blinded treatment up to Week 96.

In a cumulative analysis of all patients treated through 96 weeks, 94 percent of patients in the entecavir treatment group (n=325) experienced virologic suppression to undetectable levels, compared to 77 percent of patients given lamivudine (n=313) (p<0.0001). Additionally, the proportion of patients achieving or maintaining ALT level normalization was 89 percent for patients treated with entecavir, compared to 84 percent of patients treated with lamivudine (p=0.05).

No evidence of entecavir resistance was identified in patients treated for up to 96 weeks who had no prior lamivudine-resistance substitutions at baseline.
Safety was comparable between the treatment groups, with similar incidence of serious adverse events (6 percent with entecavir, 8 percent with lamivudine) and any adverse event (76 percent with entecavir, 80 percent with lamivudine).

Discontinuations due to adverse events were observed in 2 percent of patients treated with entecavir and 3 percent of patients treated with lamivudine. The incidence of ALT flares in patients treated with entecavir on- or off-treatment were <1 percent and 8 percent, respectively, and in patients treated with lamivudine were 2 percent and 11 percent, respectively.

These 96-week results of Study ETV-027 are an update to the 48-week study results recently published in the March 9, 2006 issue of The New England Journal of Medicine.

As part of Study ETV-026, a multinational Phase III clinical trial, 286 lamivudine-refractory, HBeAg-positive chronic hepatitis B patients were randomized to receive entecavir 1.0 mg once daily (n=141) or continued lamivudine 100 mg once daily (n=145) for a minimum of 52 weeks.

At Week 52, patients were categorized into one of three groups based on evaluations at Week 48: non-responders (HBV DNA by branched DNA ≥0.7 MEq/mL) who discontinued treatment; responders (HBV DNA by bDNA <0.7 MEq/mL and HBeAg loss) who discontinued treatment and were followed for 24 weeks off-treatment; and virologic responders (HBV DNA by bDNA <0.7 MEq/mL and but HBeAg-positive) who went on to receive blinded treatment up to Week 96.

In a cumulative analysis of all patients treated through 96 weeks, 30 percent of patients treated with entecavir (n=141) compared to less than 1 percent of patients who continued treatment with lamivudine (n=145) achieved an undetectable viral load. The difference was statistically significant (p<0.0001).

Additionally, 17 percent of entecavir patients compared to 6 percent of lamivudine patients experienced HBeAg seroconversion (p=0.0011). The proportion of patients achieving ALT normalization was significantly greater for patients treated with entecavir (85 percent), compared to patients treated with lamivudine (29 percent) (p=0.0001).

Table

Cumulative Confirmed Virologic, Serologic, and Biochemical Endpoints Through Week 96 (%)
	ETV 1.0 mg N=141	LVD 100 mg N=145	p-value
HBV DNA <300 copies/mL	30	1	<0.0001
HBeAg seroconversion	16	4	0.0011
ALT ≤1 x ULN	85	29	<0.0001

Viral rebound due to entecavir resistance mutations occurred in 9 percent of lamivudine-refractory patients during the second year of treatment.
Safety was comparable between the treatment groups, with similar incidence of serious adverse events (11 percent with entecavir, 7 percent with lamivudine) and any adverse event (83 percent with entecavir, 80 percent with lamivudine).

Discontinuations due to adverse events were observed in 1 percent of patients treated with entecavir versus 7 percent of patients treated with lamivudine. The incidence of ALT flares in patients treated with entecavir on- or off-treatment were 1 percent and 12 percent, respectively, and in patients treated with lamivudine were 11 percent and 0 percent, respectively.

The global entecavir clinical trial program was the first large-scale Phase III program to compare two antivirals, entecavir and lamivudine (the most commonly used oral antiviral therapy for the treatment of chronic hepatitis B worldwide) in the treatment of hepatitis B and involved more than 1,600 patients on five continents.

Additional clinical studies investigating entecavir use in more than 850 patients were conducted at five centers in China, where chronic hepatitis B is endemic. More than half of patients who took part in clinical trials for entecavir were from China.

Bristol-Myers Squibb is continuing to evaluate and monitor consenting chronic hepatitis B patients who participated in the entecavir clinical trial program.

In the United States, Bristol-Myers Squibb offers a Patient Assistance Program (PAP) designed to provide access to entecavir for patients who meet certain financial criteria and who either lack prescription coverage, are not eligible for Medicare or Medicaid or whose formularies do not cover entecavir. More information on the PAP program is available by calling 800-272-4878.

To learn more about entecavir (Baraclude) and for Full Prescribing Information, including boxed WARNINGS, please visit www.bms.com.

References
M. Sherman, P. Martin, W. M. Lee, and others. ENTECAVIR RESULTS IN CONTINUED VIROLOGIC AND BIOCHEMICAL IMPROVEMENT AND HBEAG SEROCONVERSION THROUGH 96 WEEKS OF TREATMENT IN LAMIVUDINE-REFRACTORY, HBEAG(+) CHRONIC HEPATITIS B PATIENTS (ETV-026). Abstract 478. DDW 2006. May 20-25, 2006. Los Angeles, CA.