Power With a Purpose by OEM65

NEW in the treatment of chronic hepatitis B (CHB)

Power with a purpose

Early Response. Powerful Performance.

FAVORABLE SAFETY & CONVENIENCE

INTRODUCING SEBIVO— UNITING THE CRITICAL ELEMENTS OF TREATMENT FOR IMPROVED DISEASE CONTROL

SUBJECT TO NP4 REVIEW AND COMPLIANCE WITH LOCAL LAWS AND REGULATIONS

Early Response. Predictable Performance.

CHB Overview

Powerful Efficacy

Rapid Response

Favorable Safety & Convenience

Predictable Outcomes

In the REVEAL study, the HBV DNA level corresponded directly to the risk of disease progression1*

CHB Overview

It’s time for higher expectations in managing CHB

High viral load leads to serious consequences of CHB

GOALS FOR SUCCESSFUL ANTIVIRAL THERAPY

Powerful Efficacy 3

• High viral load (≥105) is associated with increased mortality from HCC and chronic liver disease, which strike 15% to 40% of all patients with CHB1,2 The primary goal of antiviral therapy is HBV suppression to the lowest possible level3 IN THE CALM STUDY, HBV DNA SUPPRESSION REDUCED DISEASE PROGRESSION4‡

Disease Progression (patients, %)

P<0.001

20 15

Placebo O

Less Progression

Lamivudine O

Rapid Response5 • R apid antiviral efficacy provides: —Early indication of treatment success —Correlation with improved long-term outcomes Predictable Outcomes5 • PCR negativity at 24 weeks predicts: —Higher HBeAg seroconversion rates —Higher ALT normalization —Lower resistance Favorable Safety & Convenience • C lean preclinical profile • Well tolerated in clinical trials • One tablet, once a day, with or without food for improved compliance

5 0

• P otent viral suppression/ PCR negativity • HBeAg seroconversion • ALT normalization • H istologic improvement/ regression of fibrosis

Time (months)

Go beyond potency with rapid response that predicts outcomes5 Driving down HBV DNA with a potent therapy increases the likelihood of successful treatment outcomes3 * Ten-year prospective cohort study of 2354 CHB patients. † Hepatocellular carcinoma. ‡ Study of 651 HBeAg-positive or HBeAg-negative patients randomly assigned to receive lamivudine (n=436) or placebo (n=215).

Rapid Suppression

Predictable Outcomes

PCR negativity at 24 weeks predicts increased therapeutic success at 1 year 5

SUBJECT TO NP4 REVIEW AND COMPLIANCE WITH LOCAL LAWS AND REGULATIONS

Efficacy

Favorable Safety & Convenience

SEBIVO—powerful viral suppression ensures greater control over CHB Superior viral load reduction in GLOBE, the largest trial to date (N=1367) for CHB6*

Serum HBV DNA (Mean log10 change from baseline)

MEAN CHANGE IN HBV DNA FROM BASELINE HBeAg-POSITIVE PATIENTS (n=921) 0

P<0.0001

-1 -2 -3 -4

Lamivudine O

-5 -6

-5.5 log10

10X

-6.5 log10

-7 0

Greater Viral Suppression

SEBIVO Weeks 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 7

undectableHBV_Global_623 More of your patients can achieve PCR negativity with SEBIVO Potent viral suppression means the majority of your patients can become PCR negative6*‡ PCR NEGATIVITY (HBV DNA <300 COPIES/mL) AT 1 YEAR IN HBeAg-POSITIVE PATIENTS (n=921)

Patients With Undetectable HBV Levels (%)

Predictable Outcomes

HBeAg-Positive Patients

Rapid Response

60 %

20%

more patients achieved PCR negativity with SEBIVO than with lamivudine

40 %

40 20 0

SEBIVO (n=458)

Lamivudine (n=463)

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 Weeks

Weeks

• 75% of HBeAg-positive patients treated with SEBIVO achieved therapeutic response at 1 year vs 67% of patients treated with lamivudine (P=0.0047) 6 § *First-year results of the international GLOBE trial—the largest drug registration trial to date for CHB. GLOBE was a phase 3 comparative trial of SEBIVO vs lamivudine for CHB. Enrolled ITT population included 1367 patients. Patients were randomized to either SEBIVO (n=680 [458 HBeAg-positive, 222 HBeAg-negative patients]) or lamivudine (n=687 [463 HBeAg-positive, 224 HBeAg-negative patients]).

SEBIVO delivers rapid, profound viral suppression6* † WEEK 4

WEEK 24

WEEK 52

-4.3

-6.4

-6.5

log10

P<0.0001

Efficacy

HBeAg-Positive Patients

Powerful Efficacy

log10

These data represent mean viral load reduction at weeks 4, 24, and 52 PCR negativity was defined as HBV DNA <300 copies/mL. § Therapeutic response was a composite serologic end point at 1 year requiring suppression of HBV DNA to <5 log10 in conjunction with either loss of HBeAg or normal ALT. † ‡

SUBJECT TO NP4 REVIEW AND COMPLIANCE WITH LOCAL LAWS AND REGULATIONS

Early Response. Predictable Performance.

Efficacy

Proven Safety Profile Favorable Safety & Convenient & Convenience

Overall e antigen response with SEBIVO is impressive6,7

26% 23%

of all patients treated with SEBIVO experienced HBeAg loss at 1 year 6,7 of all patients treated with SEBIVO experienced HBeAg seroconversion at 1 year 6,7

Rapid Suppression

Higher HBeAg Seroconversion

Patients treated with SEBIVO who achieved PCR negativity at 24 weeks (n=183) experienced higher rates of HBeAg seroconversion at 1 year 8 HBeAg SEROCONVERSION AT 1 YEAR BASED ON VIRAL SUPPRESSION AT 24 WEEKS IN HBeAg-POSITIVE PATIENTS (n=425)

Almost 90% of patients treated with SEBIVO were PCR negative at 1 year 6* TIME TO PCR NEGATIVITY (HBV DNA <300 COPIES/mL) IN HBeAg-NEGATIVE PATIENTS (n=446)

PCR negative at 24 weeks P<0.0129

80 SEBIVO O

60 Lamivudine O

40 20 0

SEBIVO provides early, profound viral suppression6† WEEK 8

10 %

-4.4

2% PCR negative

Weeks

30 %

(<300 copies/mL) (n=183)

88% PCR negative at 1 year P<0.0001

80%

100

39 %

Rapid, powerful viral suppression leads to higher maintained PCR negativity

Maintained PCR Negativity (patients, %)

Predictable Outcomes Predictable Outcomes

HBeAg-Negative Patients

Rapid Response Rapid Response

SEBIVO—early viral suppression predicts higher HBeAg seroconversion

HBeAg Seroconversion at 1 Year

HBeAg-Positive Patients

Powerful Efficacy Powerful Efficacy

300 copies/mL to 3 log (n=54)

3 to 4 log (n=81)

log10

WEEK 24

-5.2

log10

WEEK 52

-5.2

log10

>4 log (n=107)

• Therapeutic response was comparable among HBeAg-negative patients treated with SEBIVO and lamivudine (75% vs 77%, respectively) 6 †‡ * PCR negativity was defined as HBV DNA <300 copies/mL. † These data represent mean viral load reduction at weeks 8, 24, and 52. ‡ Therapeutic response was a composite serologic end point at 1 year requiring suppression of HBV DNA to <5 log10 in conjunction with either loss of HBeAg or normal ALT.

SerocInclineChart_623.ai

SUBJECT TO NP4 REVIEW AND COMPLIANCE WITH LOCAL LAWS AND REGULATIONS

Early Response. Predictable Performance.

ALT/Histology

Powerful Efficacy Powerful Efficacy

Rapid Response Rapid Response

Predictable Outcomes Predictable Outcomes

Proven Safety Profile Favorable Safety & Convenient & Convenience

ALT Normal Chart6_23

SEBIVO improves liver histology in the majority of patients

Powerful viral suppression leads to ALT normalization6

ALT Normal Chart6_23

improves liver histology* at 1 year regardless of 69% SEBIVO HBeAg status

ALT NORMALIZATION AT 1 YEAR WITH SEBIVO

IMPROVEMENT

100

Patients (%)

77%

SEBIVO halts or reverses fibrosis at 1 year7†

74%

CHANGE IN ISHAK FIBROSIS SCORE AT 1 YEAR WITH SEBIVO

60 40

80 %

82%

20 0

HBeAg-Positive Patients (n=458)

Patients (%)

60 HBeAg-Negative Patients (n=222)

3 OUT OF 4 90 % 79 %

Higher ALT Normalization

34%

NO PROGRESSION

HBeAg-Positive Patients (n=399)

HBeAg-Negative Patients (n=205)

of HBeAg-positive patients treated with SEBIVO who achieved PCR negativity at 24 weeks experienced ALT normalization at 1 year 8

Change in Ishak fibrosis score at 1 year for patients treated with lamivudine: • 46% and 32% of HBeAg-positive patients experienced improvement or no change, respectively 7

of HBeAg-negative patients treated with SEBIVO who achieved PCR negativity at 24 weeks experienced ALT normalization at 1 year 8

• 44% and 43% of HBeAg-negative patients experienced improvement or no change, respectively 7

PATIENTS TREATED WITH SEBIVO ACHIEVED ALT NORMALIZATION AT 1 YEAR

39 %

NO PROGRESSION

48 %

IMPROVEMENT

• 79% of HBeAg-negative patients (n=224)

Rapid Suppression

ALT/Histology

Patients treated with lamivudine who experienced ALT normalization at 1 year 6,7: • 75% of HBeAg-positive patients (n=463)

41%

IMPROVEMENT

*Histologic response: ≥2-point decrease in Knodell necroinflammatory score from baseline with no worsening of Knodell fibrosis score. † Ishak fibrosis score: improvement defined as ≥1-point reduction in Ishak fibrosis score from baseline to week 52.

SUBJECT TO NP4 REVIEW AND COMPLIANCE WITH LOCAL LAWS AND REGULATIONS

Early Response. Predictable Performance.

Resistance/Preclinical Safety Profile

Powerful Efficacy Powerful Efficacy

Rapid Response Rapid Response

Predictable Outcomes Predictable Outcomes

Proven Safety Profile Favorable Safety & Convenient & Convenience

Powerful viral suppression minimizes resistance with SEBIVO

SEBIVO—a favorable preclinical safety profile

The superior potency of SEBIVO leads to significantly lower resistance6

SEBIVO has shown no genotoxicity, carcinogenicity, or teratogenicity11,12 RESULTS OF PRECLINICAL SAFETY TESTS FOR NUCLEOSIDE/NUCLEOTIDE ANALOGS13-16

OVERALL HBV RESISTANCE AT 1 YEAR (n=630)

SEBIVO

3 % (P=0.0007)

HBeAg Positive (n = 438)

SEBIVO

2% (P=0.0052)

HBeAg Negative (n =192)

Minimal Resistance

of HBeAg-positive patients treated with SEBIVO who achieved PCR negativity at 24 weeks developed resistance at 1 year 8

Positive finding of in vitro human lymphocyte chromosome aberration assay

Positive finding of increased rate of non-HCC tumors in oral carcinogenicity studies in mice and rats §

Positive finding of in vitro human lymphocyte chromosome aberration and in vitro mouse lymphoma cell assays

No risk of carcinogenicity was shown in rat and mouse studies

No evidence of genotoxicity was shown in in vitro or in vivo studies

No risk of carcinogenicity was shown in bioassay studies

Adefovir *

• No activity was noted against multiple other RNA and DNA viruses (including HIV) in vitro Not incorporated into human DNA11 • Selectively terminates HBV with low affinity for human DNA in vitro

Lamivudine

Resistance/Preclinical Safety Profile

L80I/V L180M A181V A184G S202I M204I + M204V + N236T M250V M204I M204V

†

T he theoretical concern for an increased risk of non-hepatocellular carcinoma cancers to humans based on the carcinogenicity findings in rodents will be addressed in a large, randomized, prospective, observational study with long-term follow-up.16

Potent antiviral activity specific to HBV11

HEPATITIS B POLYMERASE MUTATIONS ASSOCIATED WITH VIROLOGIC REBOUND BY TREATMENT

SEBIVO

No risk of carcinogenicity was shown in rat and mouse studies

SEBIVO has a preference for inhibiting + strand synthesis17

The key polymerase mutation associated with breakthrough to SEBIVO is M204I

†

Carcinogenicity Studies

SEBIVO—a potent and selective nucleoside analogue

of HBeAg-negative patients treated with SEBIVO who achieved PCR negativity at 24 weeks developed resistance at 1 year 8

Entecavir

Positive finding of in vitro human lymphocyte chromosome aberration and in vitro mouse lymphoma cell assays

SEBIVO

Rapid Suppression

Adefovir

Lamivudine

• 9% of HBeAg-negative patients (n=187)

Genotoxicity Studies

Entecavir

Patients treated with lamivudine experienced significantly higher rates of resistance at 1 year 6 : SEBIVO activity is only patients reduced against • 8% of HBeAg-positive (n=442)M204I pathway7

0% 1%

Treatment

SEBIVO

inhibits + strand HBV DNA synthesis

‡

*Mutations at A184G or S202I or M250V in addition to L180M+M204V may be required to confer resistance to entecavir. † M204I by itself has not been associated with clinical breakthrough to entecavir, but is resistant in vitro. ‡ L180M+M204V has not been associated with clinical breakthrough to SEBIVO, but is resistant in vitro.

SUBJECT TO NP4 REVIEW AND COMPLIANCE WITH LOCAL LAWS AND REGULATIONS

Early Response. Predictable Performance.

Tolerability/Convenience

Powerful Efficacy Powerful Efficacy

Rapid Response Rapid Response

Predictable Outcomes Predictable Outcomes

Proven Safety Profile Favorable Safety & Convenient & Convenience

SEBIVO—a favorable safety and tolerability profile

A convenient therapy that’s easy for your patients to take

In the GLOBE study (N=1367), the incidence of adverse events associated with SEBIVO was similar to lamivudine for up to 104 weeks7

Greater convenience leads to improved patient compliance DOSING & ADMINISTRATION13-16,18

SELECTED TREATMENT-EMERGENT CLINICAL ADVERSE EVENTS (GRADE 2-4)

Adverse Event

SEBIVO (n=680)

Lamivudine (n=687)

All Subjects Muscle-Related Symptoms Fatigue/Malaise Headache Pyrexia Abdominal Pain Arthralgia Cough Diarrhea Gastritis

22% 2% 1% 1% 1% <1% <1% <1% <1% <1%

22% 2% 1% 2% <1% <1% 1% <1% <1% 0%

In the GLOBE study, SEBIVO showed no nephrotoxicity, similar to lamivudine. Lower rate of discontinuation vs lamivudine7 •O nly 0.6% of patients taking SEBIVO discontinued therapy due to adverse events, clinical disease progression, or lack of efficacy vs 2.0% of patients taking lamivudine 5.5 times fewer ALT flares vs lamivudine •O nly 0.4% of patients treated with SEBIVO experienced ALT flares from week 24 to week 52 vs 2.2% of patients treated with lamivudine (P=0.0002) 7

Oral Administration

No Food Effect

Adefovir Administer on an empty stomach (at least 2 hours after a meal and 2 hours before the next meal)

Entecavir Lamivudine Peg-Interferon

Once weekly

Subcutaneous injection in the abdomen or thigh

SEBIVO REFERENCES: 1. Chen G, Lin WY, Shen FM, Iloeje UH, London WT, Evans AA. Viral load as a predictor of mortality from hepatocellular carcinoma and chronic liver disease in chronic hepatitis B infection. Presented at: 40th Annual Meeting of the European Association for the Study of the Liver. April 13-17, 2005; Paris, France. 2. Chen C-J, Yang H-I, Su J, et al, for the REVEAL-HBV Study Group. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006;295:65-73. 3. Keeffe EB, Dieterich DT, Han S-HB, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States. Clin Gastroenterol Hepatol. 2004;2:87-106. 4. Liaw Y-F, Sung JJY, Chow WC, et al, for the Cirrhosis Asian Lamivudine Multicentre Study Group. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004;351:1521-1531. 5. Lai C-L, Gane E, Liaw Y-F, et al, and the GLOBE Study Group. Maximal early HBV suppression is predictive of optimal virologic and clinical efficacy in nucleoside-treated hepatitis B patients: scientific observations from a large multinational trial (the GLOBE Study). Presented at: American Association for the Study of Liver Diseases; November 11-15, 2005; San Francisco, Calif. 6. Lai C-L, Gane E, Thongsawat S, et al, and the GLOBE Study Group. Telbivudine (LdT) vs lamivudine in the treatment of chronic hepatitis B: results from GLOBE, an international phase III trial. Poster presented at: Shanghai-Hong Kong International Liver Congress; March 25-28, 2006; Shanghai, China. Poster 182. 7. US Tyzeka Prescribing Information. 8. Di Bisceglie A, Lai C-L, Gane E, et al, and the GLOBE Study Group. Maximal HBV suppression in the first six months is associated with optimal virologic and clinical efficacy at one year in nucleoside-treated hepatitis B patients. Presented at: Hep DART 2005; December 11-15, 2005; Kohala Coast, Big Island, Hawaii. 9. Locarnini S, Hatzakis A, Heathcote J, et al. Management of antiviral resistance in patients with chronic hepatitis B. Antivir Ther. 2004;9: 679-693. 10. Standring DN, Seifer M, Patty A, et al. HBV resistance determination from the telbivudine GLOBE registration trial. Poster presented at: 41st Annual Meeting of the European Association for the Study of the Liver; April 26-30, 2006; Vienna, Austria. Poster 514. 11. Standring DN, Bridges EG, Placidi L, et al. Antiviral b-l-nucleosides specific for hepatitis B virus infection. Antivir Chem Chemother. 2001;12(suppl 1):119-129. 12. Bridges EG. Telbivudine preclinical safety studies suggest minimal risk of chronic toxicity, reproductive toxicity, or carcinogenicity. Poster presented at: Shanghai-Hong Kong International Liver Congress; March 25-28, 2006; Shanghai, China. Poster 179. 13. Baraclude Prescribing Information. 14. Hepsera Prescribing Information. 15. Epivir Prescribing Information. 16. Zhou X-J, Lloyd DM, Chao GC, Brown NA. Absence of food effect on the pharmacokinetics of telbivudine following oral administration in healthy subjects. J Clin Pharmacol. 2006;46:275-281. 17. Seifer M, Patty A, Dukhan D, et al. Telbivudine (LdT) preferentially inhibits second (+) strand HBV DNA synthesis. Presented at: 40th Annual Meeting of the European Association for the Study of the Liver; April 13-17, 2005; Paris, France. 18. Pegasys Prescribing Information.

Treatment SEBIVO

NONE

Entecavir Adefovir

Lamivudine

•A s with other therapies in this class, cases of myopathy have been reported with SEBIVO several weeks to months after starting therapy 12

SUBJECT TO NP4 REVIEW AND COMPLIANCE WITH LOCAL LAWS AND REGULATIONS

Early Response. Predictable Performance.

Tolerability/Convenience

Additional findings •T he most common grade 3-4 lab abnormality seen with SEBIVO was elevations in creatinine kinase (9.0% vs 3.0% with lamivudine). Most CK elevations were asymptomatic but the mean recovery time was slightly longer for subjects taking SEBIVO than subjects taking lamivudine 7

One Tablet/ Once Daily

Your patients deserve a therapy that delivers power with a purpose Give your patients an uncompromising treatment choice with SEBIVO Powerful Efficacy 6 • Potent viral suppression/ PCR negativity

Rapid Response7 • Rapid antiviral efficacy provides:

• HBeAg seroconversion

— Early indication of treatment success

• ALT normalization

— Correlation with improved longterm outcomes

• Histologic improvement/ regression of fibrosis

Predictable Outcomes7

Favorable Safety & Convenience 6

• PCR negativity at 24 weeks predicts:

• Clean preclinical profile

— Higher HBeAg seroconversion rates

• Well tolerated in clinical trials

— Higher ALT normalization

• One tablet, once a day, with or without food for improved compliance

—Lower resistance

Early Response. Predictable Performance.