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PEGASYS® HCV Global Slide Kit

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Slide 3. PEGASYS®: large, branched 40KD PEG attached by stable bonds

•PEGASYS® has a large, branched, 40KD polyethylene glycol (PEG), attached to interferon alfa-2a by a stable amide bond. Biological activity is retained as accessibility of the interferon binding site is maintained. •The large size of the 40KD PEG moiety results in prolonged half-life and restricts its volume of distribution. Thus, the distribution of PEGASYS® is limited to the blood and organs well perfused with blood, such as the liver. PEGASYS® also has reduced clearance compared with conventional interferon alfa.

Slide 4. PEGASYS® maintains consistent plasma levels over a week

•PEGASYS® is associated with antiviral coverage that is sustained throughout the weekly dosing interval. •After one subcutaneous injection of PEGASYS® 180 μg, the serum drug level reaches a maximum concentration of 14.2 ng/mL (bottom curve).1 Unlike the drug concentration-time curve for unpegylated interferons2, serum concentrations of PEGASYS® are constant and sustained throughout the week. •Until steady state is reached (5 to 9 weeks), serum concentrations more than double and are constant and sustained throughout the week.3 After steady state is reached, further drug accumulation does not occur (the amount of PEGASYS® eliminated from the body equals the amount entering via administration). The concentration-time curve for the week 9 injection (not shown) would be similar to that for the week 48 injection (top curve).3 •Once the entire treatment course with PEGASYS® 180 μg once weekly has been completed, the serum concentration levels slowly descend; complete elimination of the drug occurs within 50 to 60 days post-treatment.3

1. Algranati N, et al. Hepatology 1999; 30(Suppl 2): 190A

2. Koslowski A, et al. BioDrugs 2001; 15: 419

3. Modi M, et al. Hepatology 2000; 32(Suppl): 394

Slide 5. PEGASYS® (Peginterferon Alfa-2a [40KD])

Need Not Be Dosed by Weight

PEGASYS® (peginterferon alfa-2a [40KD]) has a restricted distribution and is predominantly found in the bloodstream and interstitial fluid rather than in the tissues.1 Its volume of distribution is small (8 to 12 L).2

Because its maximum tolerated and minimum effective doses are widely separated, PEGASYS® has a broad therapeutic index.1

In an analysis of patient variability in volume of distribution and clearance of PEGASYS® in relation to body surface, body weight, and body mass index, body weight accounted for less than 1% of the observed between-patient variability in these pharmacokinetic parameters.1

Moreover, the efficacy and safety of PEGASYS® are not altered by variations
in patient body weight.1

1. Lamb MW, Martin NE. Ann Pharmacother. 2002;36:933-935. 2. Perry CM, Jarvis B. Drugs. 2001;61:2263-2288.

Slide 6: Summary of pharmacokinetics (PK)

•This table compares the pharmacokinetics of three molecules: conventional interferon alfa, small linear pegylated interferon alfa-2b (12KD) and PEGASYS®. •Conventional interferon alfa has a very short half-life of 3–8 hours, so within 24 hours there is little interferon alfa left in the serum. The peak-trough ratio is infinity which means that there are huge fluctuations in interferon alfa serum concentrations which are associated with side effects of therapy and viral rebound. Pegylated interferon alfa-2b (12KD) has a longer serum half-life of approximately 40 hours and approximately a 10-fold reduced clearance rate compared with conventional interferon alfa. This molecule has a peak-trough ratio of approximately 100:1 which still indicates wide fluctuation in serum concentrations across the dosing interval. •With the use of a 40KD PEG in PEGASYS®, the resulting molecular entity has a much lower volume of distribution, reduced clearance, an increased half-life of approximately 80 hours and a low peak-to-trough ratio. PEGASYS® exhibits sustained plasma levels over the entire dosing interval.

1. Perry C, Jarvis B. Drugs 2001; 61: 2263

2. Glue P, et al. Clin Pharmacol Ther 2000; 68: 556

3. PEG-Intron™ PDR®

4. ROFERON®-A PDR®

5. Reddy K. Ann Pharmacother 2000; 34: 915

6. Hoffmann-La Roche. PEGASYS® Monograph

7. INTRON® A PDR®

Slide 14. End-stage Renal Disease

HCV infects 10–20% of end-stage renal disease (ESRD) patients undergoing haemodialysis.

The patients often have impaired adsorption, distribution, metabolism and clearance which can lead to an increase in adverse events and high discontinuation rates. Ribavirin (RBV) is contraindicated in these patients.

Improved benefit for ESRD patients may be offered by newer therapies such as PEGASYS® (40KD), that have similar efficacy to conventional IFN/RBV therapy, but without the side effects associated with use of RBV.

Slide 16 Renal Impairment

Renal impairment does necessitate adjusting the dose of PEG-Intron™ (peginterferon alfa-2b [12KD]) in individuals with creatinine clearance less than 50 mL/min.

In contrast, reported pharmacokinetic results for PEGASYS® (peginterferon alfa-2a [40KD]) indicate that no change in dosing is required for patients with creatinine clearance >20 mL/min.2

Martin and associates administered single 90-mg doses of PEGASYS® to one group of normal subjects and five groups of patients with varying degrees of renal impairment. Their analysis indicated that creatinine clearance of
40 mL/min or less and greater than 20 mL/min had only slight effects on the pharmacokinetic profile for PEGASYS®, and that patients with creatinine clearance greater than 20 mL/min required no dose adjustments.2

1. PEG-Intron™. PDR ®. 56th ed. 2002. 2. Martin P et al. Hepatology. 2000;32 (suppl):370A.

Slide 18. Possible side effects of interferon treatment

•A wide range of clinical symptoms and laboratory abnormalities have been associated with interferon treatment. •Adverse reactions include flu-like symptoms (headache, fatigue or asthenia, myalgia, arthralgia, fever, chills), nausea, anorexia, diarrhoea, psychiatric symptoms (depression, insomnia), alopecia and injection-site reactions. •Interferon treatment may also result in leukopenia, thyroiditis, autoimmunity and thrombocytopenia.

1. INTRON® A. PDR®

2. ROFERON®-A. PDR®

Slide 19. Possible side effects of ribavirin treatment

•Treatment with ribavirin has also been associated with a number of adverse events, including haemolytic anaemia, cough, dyspnoea, rash, pruritus, insomnia, ataxia, anorexia and teratogenicity.1,2

1. REBETOL®. PDR®

2. Chutaputti A. J Gastroenterol Hepatol 2000; 15(suppl): E156