丙肝的治疗策略——药物的选择 厦门市第三医院 马龙教授

学习目标 掌握聚乙二醇干扰素的优越性 掌握聚乙二醇干扰素与普通干扰素的差异 掌握聚乙二醇干扰素α-2a（派罗欣）和聚乙二醇干扰素α-2b（佩乐能）的差异

病例1 患者1：男性，45岁，10年前输血感染丙肝，治疗前检查：肝功能112IU/L，HCV RNA 3×10*6拷贝/毫升，基因分型为基因1型，血常规白细胞、血红蛋白均、甲状腺功能均正常。两年前选择了普通干扰素治疗，治疗3个月、6个月时复查HCV RNA，均未见转阴，患者坚持治疗至一年，病毒仍为阳性。宣告治疗失败，停止治疗。 患者2：男性，48岁，也是10年前输血感染的丙肝，治疗前检查：肝功能120IU/L，HCV RNA 6×10*7拷贝/毫升，基因分型为基因1型，血常规白细胞、血红蛋白均、甲状腺功能均正常。由于经济条件比较好，为了追求最佳的治疗效果，患者选择了派罗欣治疗，治疗3个月时复查HCV RNA即已转阴，但患者仍然坚持完成了一年的治疗，治疗结束后随访半年病毒仍为阴性。

问题1 聚乙二醇干扰素与普通干扰素之间有何不同？ 聚乙二醇干扰素的血药浓度较之普通干扰素更稳定 聚乙二醇干扰素一周注射一次，使用更方便，用药依从性更好 聚乙二醇干扰素临床疗效更高 以上全是

聚乙二醇干扰素与普通干扰素的对比

慢性丙肝治疗的进展——普通干扰素时代 SVR<40% 罗氏首个普通干扰素α产品上市 FDA批准罗扰素用于临床治疗慢性丙肝 普通干扰素+利巴韦林方案有更好的疗效4 1986 1989 1991 1993 1994 1997 普通干扰素首次治疗非甲非乙型肝炎，并验证有效1,2 普通干扰素48周疗程的疗效优于24周3 NIH提出普通干扰素治疗慢性丙肝的标准方案5 SVR<20% 1.Davis et al. NEJM 1989；2.DiBisceglie et al. NEJM 1989; 3. Saracco G, et al. Hepatology. 1993; 18(6): 1300-5; 4. Brillanti S, et al. 1994; 107(3): 812-7; 5. http://consensus.nih.gov/1997/1997HepatitisC105html.htm.

普通干扰素的缺陷 血药浓度波动明显，无法持续发挥作用 血清 IFN 水平 (U/mL) 时间 高剂量用药 1周 Perry C, Jarvis B. Drugs 2001; 61: 2263; Glue P, et al. Clin Pharmacol Ther 2000; 68: 556

普通干扰素α用于丙肝治疗的局限 普通干扰素单药治疗慢性丙肝的SVR率基本不超过20% 派罗欣HCV Global Slide Kit 普通干扰素α用于丙肝治疗的局限 普通干扰素单药治疗慢性丙肝的SVR率基本不超过20% 普通干扰素+利巴韦林联合治疗慢性丙肝的SVR率基本不超过40% 临床亟待一种更为高效的慢性丙肝治疗方案，从而提高临床总体SVR率

慢性丙肝治疗的进展——派罗欣时代 派罗欣是治疗慢性丙肝的标准用药 罗氏派罗欣全球上市 NIH推荐派罗欣+利巴韦林作为丙肝治疗的金标准2 G1: SVR约40–50% G2/3: SVR约80% 罗氏派罗欣全球上市 NIH推荐派罗欣+利巴韦林作为丙肝治疗的金标准2 获得国际多中心临床试验最高总体SVR率66％4 派罗欣是治疗慢性丙肝的标准用药 2002 2004 2005 2007 至今 III期临床派罗欣疗效全面优于普通干扰素1 制定慢性丙肝标准治疗方案3 证实派罗欣治疗获得SVR即为“治愈”5 1.Fried MW et al. N Engl J Med. 2002; 347(13): 975-82；2. http://consensus.nih.gov/2002/2002HepatitisC2002116main.htm; 3.Hadziyannis SJ, et al. Ann Intern Med. 2004; 140(5): 346-55；4.Zeuzem S, et al. J Hepatol. 2005; 43(2): 250-7; 5.Swain et al, EASL 2007

派罗欣分子的创新设计 第二代PEG干扰素 大分子支链 PEG干扰素(40KD) 修饰 减少抗体 阻止蛋白降解 降低给药频率 延长半衰期

更好的药代动力学 ——整个疗程派罗欣的血浆水平保持稳定 派罗欣HCV Global Slide Kit 首次给药后1 到达稳态时2 30 25 20 派罗欣 180 mg qw 15 平均浓度 (ng/mL) 10 5 Slide 11. 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 24 48 72 96 120 144 168 小时 治疗5～9周时，达到稳态浓度后，派罗欣在血清中无累积 1. Algranati N, et al. 49th AASLD 1999；2. Modi M, et al. 50th AASLD 2000

更好的病毒动力学 ——派罗欣持续抑制病毒水平，不发生反弹 派罗欣HCV Global Slide Kit 5 10 15 –0.5 –1 –1.5 HCV RNA 水平相对于基线值的平均改变 (log10) Slide 12. PEGASYS® plus VX-950 leads to rapid viral load decline without viral rebound In contrast to results seen with pegylated interferon alfa-2b (12KD) and new molecules for the treatment of hepatitis C, PEGASYS® has been associated with consistent and substantial viral load decline, consistent with sustained serum concentrations over the entire once-weekly dosing interval. VX-950 is a highly selective peptidomimetic inhibitor of the HCV NS3-4A protease that is designed to stop virus replication with a shorter treatment duration than current pegylated interferons. VX-950 monotherapy has been shown to have substantial antiviral effects which are increased with the addition of PEGASYS®. As can be seen from the figure, decreases in HCV RNA are sustained with all three regimens. Reesink H, et al. 41st EASL 2006; Abstract 737 治疗天数 Reesink H, et al. 41st EASL 2006; Abstract 737

慢性丙肝治疗的里程碑 聚乙二醇干扰素实现了最高的总体SVR率——66% 派罗欣HCV Global Slide Kit 70 66 60 54 50 44 41 SVR率(%) 40 30 25 20 13 10 普通干扰素 1998年1 PEG-IFNα-2b (12KD) 2001年2 派罗欣® 2004年3 普通干扰素 + 利巴韦林 2002年4 PEG-IFNα-2b (12KD) +利巴韦林20015 派罗欣® +利巴韦林 2005年6 单药治疗方案 联合治疗方案 1. McHutchison JG et al. N Engl J Med. 1998:1485-1492. 2. Lindsay K et al. Hepatology. 2001:395-403. 3.徐道振, 等. 中华传染病杂志. 2004; 22: 221. 4. Fried MW, et al. N Engl J Med. 2002; 347(13): 975-82. 5. Manns MP, et al. Lancet. 2001; 358(9286): 958-65. 6. Zeuzem S, et al. J Hepatol. 2005; 43(2): 250-7.

Fried研究结果： 对所有基因型和病毒载量的疗效均优于普通干扰素+利巴韦林的治疗方案 2002年 The New England Journal of Medicine Pegasys and Copegus: SVR by Genotype and Viral Load A total of 1,211 patients were randomly assigned to treatment and received Pegasys (Peg IFN alfa-2a) 180 mcg QW + Copegus (ribavirin) 1000/1200 mg/d, Pegasys + Placebo daily, or Intron A (IFN alfa-2b) 3 MIU TIW + Rebetol (ribavirin) X 48 weeks. Among patients with HCV genotype 1 and high baseline viral RNA levels (> 2 million copies/mL), 41% of those receiving Pegasys + Copegus had an SVR as compared with 33% of those receiving Intron A + Rebetol. Reference Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982. 派罗欣+利巴韦林：唯一对所有基因型和病毒载量的疗效均优于普通干扰素+利巴韦林的治疗方案 Fried MW, et al. N Engl J Med. 2002;347:975-982.

Fried研究结果： 对所有基因型和病毒载量的疗效均优于普通干扰素+利巴韦林的治疗方案 普通干扰素 3 MIU + 1000/1200 mg 利巴韦林 (n = 428) 派罗欣 180 μg + 1000/1200 mg 利巴韦林 (n = 437) 100 81% 80 74% 65% 58% 56% 60 SVR (%) 43% 41% 40 33% 20 Pegasys and Copegus: SVR by Genotype and Viral Load A total of 1,211 patients were randomly assigned to treatment and received Pegasys (Peg IFN alfa-2a) 180 mcg QW + Copegus (ribavirin) 1000/1200 mg/d, Pegasys + Placebo daily, or Intron A (IFN alfa-2b) 3 MIU TIW + Rebetol (ribavirin) X 48 weeks. Among patients with HCV genotype 1 and high baseline viral RNA levels (> 2 million copies/mL), 41% of those receiving Pegasys + Copegus had an SVR as compared with 33% of those receiving Intron A + Rebetol. Reference Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982. ≤2 x 106 >2 x 106 ≤2 x 106 >2 x 106 拷贝/mL 拷贝/mL 拷贝/mL 拷贝/mL 基因1型 基因2/3型 Fried MW, et al. N Engl J Med. 2002;347:975-982.

Manns研究： 聚乙二醇干扰素-2b(12KD)仅在低病毒载量患者中的SVR率优于普通干扰素 普通干扰素 + 利巴韦林 PEG-IFN -2b (12KD) 1.5 g/kg + 利巴韦林 90 82 79 80 68 70 60 50 43 SVR (%) 40 29 30 30 20 Slide 16. Peginterferon Alfa-2b [12KD] Plus 利巴韦林: SVR by HCV Genotype and Viral Load When evaluating SVRs by HCV genotype and viral load, investigators determined that peginterferon alfa-2b [12KD] plus 利巴韦林 was only superior to standard IFN alfa-2b plus 利巴韦林 in patients with HCV genotype 1 and low viral load.1,2 In other patient subgroups, there was no difference between treatment with peginterferon alfa-2b and standard combination therapy.1,2 Data for HCV genotype 2 or 3 patients according to low or high viral load are not publicly available.   1. PEG-Intron™. PDR ®. 56th ed. 2002. 2. Manns MP et al. Lancet. 2001;358:958-965. 10 n = 96 n = 92 n = 247 n = 256 n = 345 n = 351 ≤2x106拷贝/mL >2 x 106 拷贝/mL 基因2/3型 基因1型 Manns MP et al. Lancet. 2001;358:958-965.

小结 聚乙二醇干扰素以其优越的药代动力学实现了干扰素的血药浓度的稳定，突破了普通干扰素的局限 与普通干扰素相比，聚乙二醇干扰素- 2a优势更明显，SVR更高

聚乙二醇干扰素α-2a和聚乙二醇干扰素α-2b的对比 ——大分子与小分子的差异

病例2 患者男性，45岁，5年前由于手术输血感染丙肝，2年前开始接受抗病毒治疗，由于家庭经济条件比较好，医生为其选用了聚乙二醇干扰素α-2a联合利巴韦林的治疗方案，两个月后病毒即转阴，经一年的治疗，停药后继续随访半年，病毒仍为阴性，最终实现了SVR。

问题2： 从药代动力学及病毒动力学角度，为什么医生为其选择了聚乙二醇干扰素α-2a？ 聚乙二醇干扰素α-2a的血药浓度更稳定，依从性更高 派罗欣无需根据体重调节剂量，使用更方便 聚乙二醇干扰素α-2a的半衰期更长，用药间期也能保持很好的病毒抑制 以上都是

派罗欣®: 疗效源于设计 独有的聚乙二醇化: 大分子, 支链 40KD PEG分子 稳定的酰胺键结合方式 派罗欣可以在用药间期维持足够一周的血药浓度稳定1,2 更人性化的药物剂型 和更简单的剂量策略 Slide 21. PEGASYS®: better by design 无论是多中心的国际临床研究还是临床实践均获得最高的 SVR 应答率 1. Algranati N, et al. 49th AASLD 1999 2. Modi M, et al. 50th AASLD 2000 3. Zeuzem S, et al. J Hepatol 2005; 43: 250

释放大分子的力量 第一代PEG干扰素 小分子线性PEG干扰素（12KD） 第二代PEG干扰素 大分子支链 PEG干扰素(40KD) 修饰 半衰期更长 降低给 药频率 修饰 减少抗体 阻止蛋 白降解

两种聚乙二醇干扰素的差异 聚乙二醇干扰素α-2b (12KD) 派罗欣® (40KD) 干扰素 干扰素α-2b 干扰素α -2a PEG 结构 小分子, 线性 12KD PEG 大分子, 支链 40KD PEG 同位异构体 14 6 结合位点 氨基甲酸乙酯键，不稳定 酰胺键，更稳定 Slide 23. Differences between the two currently available pegylated interferons The two currently available pegylated interferons, PEGASYS® (40KD) and pegylated interferon alfa-2b (12KD), differ significantly in their chemical structure. PEGASYS® consists of interferon alfa-2a monopegylated with a 40KD branched polyethylene glycol (PEG) molecule. The four major positional isomers are Lys31, Lys121, Lys131 and Lys134. Ninety-four percent of the PEG attachment takes place at these four sites. The remaining ~6% of the PEG attachment takes place at Lys70 and Lys83. The amide bond between PEG and interferon alfa-2a is stable.1 Pegylated interferon alfa-2b (12KD) is formed by attaching a 12KD PEG molecule to interferon alfa-2b. Fourteen different positional isomers have been identified.2 The predominant site of pegylation is the His34 residue (~50%) with the remaining positional isomers located at various lysines, the N-terminal cysteine, serines and tyrosines.2,3 The bond between the PEG molecule and the histidine residue is labile.3,4 1. Bailon P, et al. Bioconjugate Chem 2001; 12: 195 2. Grace M, et al. J Interferon Cytokine Res 2001; 21: 1103 3. Youngster S, et al. Curr Pharm Des 2002; 8: 2139 4. Wang Y-S, et al. Biochemistry 2000; 39: 10634 1. Bailon P, et al. Bioconjugate Chem 2001; 12: 195 2. Kozlowski A, et al. BioDrugs 2001; 15: 419 3. Wang Y-S, et al. Biochemistry 2000; 39: 10634 4. Youngster S, et al. Curr Pharm Des 2002; 8: 2139 5. Grace M, et al. J Interferon Cytokine Res 2001; 21: 1103

派罗欣®: 大分子支链PEG分子以稳定的结合方式进行结合 40KD 支链PEG分子 大分子 PEG (40KD) 支链, 非线性 稳定的酰胺键结合方式 与干扰素受体的结合得以良好的保留 增加了血清半衰期 分布容积小 IFN-2a Slide 24. 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. large exclusion volume

第二代大分子PEG干扰素（40KD）派罗欣® 药代动力学的差异 药物动力学参数 第一代小分子PEG干扰素（12KD） 第二代大分子PEG干扰素（40KD）派罗欣® 分布容积，L 80 6–14 分布容积小 清除率，mL/h 1,540 80 降低清除率 吸收半衰期， h 4.6 50 持久吸收 清除半衰期，h » 40 77 延长半衰期 Slide 25. Pegylated Interferons: Pharmacokinetic Properties The pharmacokinetics of conventional IFNs differ significantly from those of pegylated IFNs (PEG-IFNs). In addition, PEG-IFN pharmacokinetics differ based on the type of pegylation employed, principally the size and nature of the PEG molecule attached. In the case of 派罗欣® (peginterferon alfa-2a [40KD]), the use of a 40-KD PEG molecule results in a molecular entity with a low volume of distribution, reduced clearance, and an increased half-life.1-6 1. Perry CM, Jarvis B. Drugs. 2001;61:2263-2288. 2. Glue P et al. Clin Pharmacol Ther. 2000;68:556-567. 3. 第一代PEG干扰素. PDR ®. 56th ed. 2002. 4. INTRON® A. PDR ®. 56th ed. 2002. 5. Reddy KR. Ann Pharmacother. 2000;34:915-923. 6. Hoffmann-La Roche. 派罗欣®. Monograph. PEG-Intron™. PDR ®. 56th ed. 2002. 2. Reddy KR Ann Pharmacother. 2000;34:915-923. 3. Hoffmann-La Roche. 派罗欣® Monograph.4. INTRON® A. PDR ®. 56th ed. 2002.

只有派罗欣®的浓度才能在用药间期维持一周的稳定浓度 保证用药间期的病毒抑制 用药间期病毒抑制不足 30 000 30 000 20 000 20 000 10 000 10 000 聚乙二醇干扰素α-2b(12KD) 3 1.5 µg/kg qw 平均浓度 (pg/mL) 平均浓度 (pg/mL) 1200 派罗欣® 1200 稳态浓度2 首剂后浓度1 800 800 Slide 26. Only PEGASYS® concentrations are sustained over the entire weekly dosing interval PEGASYS® is associated with antiviral coverage that is sustained throughout the weekly dosing interval. Serum concentrations of pegylated interferon alfa-2b (12 KD) drop to undetectable levels by the end of the week. 400 400 24 48 72 96 120 144 168 24 48 72 96 120 144 168 小时 小时 1. Algranati N, et al. 49th AASLD 1999 2. Modi M, et al. 50th AASLD 2000 3. Adapted from Glue P, et al. Clin Pharmacol Ther 2000; 68: 556

聚乙二醇干扰素α-2b(12KD)联合SCH 503034 造成一周之内病毒的反弹 聚乙二醇干扰素α-2b(12KD) 单独治疗 (n=22) 聚乙二醇干扰素α-2b(12KD) + SCH 503034 200 mg TID (n=12) 聚乙二醇干扰素α-2b(12KD) + SCH 503034 400 mg TID (n=12) –0.5 –1 Mean HCV RNA change from baseline (log10) –1.5 Slide 27. Peg-IFN alfa-2b (12KD) plus SCH 503034 leads to intraweek viral rebound The viral rebound seen in trials of pegylated interferon alfa-2b (12KD) plus ribavirin has also been reported in trials with SCH 503034, a novel HCV protease inhibitor that delivers antiviral activity in a capsule formulation. In this multicentre, open-label study, genotype 1 non-responders to pegylated interferon alfa-2b (12KD) plus ribavirin were randomised to pegylated interferon alfa-2b (12KD) alone (n=22), pegylated interferon alfa-2b (12KD) + SCH 503034 200 mg TID (n=12) or pegylated interferon alfa-2b (12KD) + SCH 503034 400 mg TID (n=12).1 Viral rebound was seen before the end of the once-weekly dosing interval. Diminished antiviral activity can lead to the emergence of resistance.2 1. Zeuzem S, et al. 56th AASLD 2005; Abstract 201 2. Havlir D, et al. JAMA 2000; 283: 229 –2 –2.5 –3 5 10 15 治疗天数 Genotype 1 non-responders to pegylated interferon plus ribavirin Zeuzem S, et al. 56th AASLD 2005; Abstract 201

大分子派罗欣集中分布于肝脏和血液 派罗欣 佩乐能 分布容积小（6－14 L） 分布容积大（69 L） 按固定剂量给药 按体重调节剂量 临床实际应用中，佩乐能并不是完全按体重给药，而是按照某个体重范围给予固定剂量，必然造成某些患者用药不足，部分患者用药过量

派罗欣预充针固定剂量，使用方便，用药依从性更高 PEG-Intron™1 PEGASYS®2 根据体重确定剂量 固定剂量 Slide 29.聚乙二醇化干扰素：剂量与给药 PEG-Intron™ (聚乙二醇化干扰素 alfa-2b [12KD])为白色冻干粉末，溶于2-ml瓶子内供皮下注射用。74-222 g PEG-Intron™溶解后在每0.5ml溶液中含50-150 g。1 PEG-Intron™ 的表观分布容积为 0.99 L/kg.2 由于体重对表观清除率以及活性有统计学上的显著影响，因而需要根据患者的体重作出剂量调整。3 PEG-Intron™ 单一用药的推荐剂量为1.0 g/kg/周，同时要按体重进行剂量调整，如下表所示。当与RBV联合用药时，推荐剂量为1.5 g/kg/周(见表）。RBV的推荐剂量为800mg/d，分两次给药。1 *When reconstituted as directed. PEGASYS® (聚乙二醇化干扰素 alfa-2a [40KD]) is dispensed as a stable solution in vials and in single-use prefilled syringes. The recommended regimen for PEGASYS® is the same fixed dose for all patients, regardless of weight, age (elderly) or liver status (cirrhotics): once-weekly sc administration of 180 g, which has been established as the optimal dose based on virological response and toxicity data.4 Because of its restricted biodistribution (8 to 12 L),4 PEGASYS® is given as a fixed dose without regard to the patient’s weight. 1. PEG-Intron™. PDR . 56th ed. 2002. 2. Glue P et al. Clin Pharmacol Ther. 2000;68:556-567. 3. Lamb MW, Martin NE. Ann Pharmacother. 2002;36:933-935. 4. Reddy KR. Ann Pharmacother. 2000;34:915-923. 5. Perry CM, Jarvis B. Drugs. 2001;61:2263-2288. 为冻干制剂 每次注射前需要溶解 为稳定的水溶液PFS 可供直接注射 PEG-IFN a-2b (12KD) Recommended Dosing1 Body Weight (kg) PEG-IFN -2b (12KD) Vial Strength Amount (mg) of PEG-IFN -2b (12KD) to Administer Volume (mL)* of PEG-IFN -2b (12KD) to Administer Recommended Monotherapy Dosing 45 46–56 50 g per 0.5 mL 40 50 0.4 0.5 57–72 73–88 80 g per 0.5 mL 64 80 89–106 107–136 120 g per 0.5 mL 96 120 137–160 150 g per 0.5 mL 150 Recommended Combination Therapy Dosing 40 41–50 51–60 61–75 76–85 >85 1. PEG-Intron™. PDR ®. 56th ed. 2002. 2. Perry CM, Jarvis B. Drugs. 2001;61:2263-2288.

超过90% 派罗欣®用户认为派罗欣®预充针使用更人性化 Patients considering administration as: 6.4% 27.7% 66.0% User-friendly Not user-friendly [missing values] Pegylated interferon alfa-2b (12KD) – injector (n=47) 7.1% 1.8% 91.1% Slide 30. Over 90% of patients using PEGASYS® pre-filled syringe consider it user-friendly This study compared the economic and handling aspects of the commercial formulations of the PEGASYS® pre-filled syringe and the pegylated interferon alfa-2b (12KD) injector. 103 patients at nine centres in Germany were given a questionnaire concerned with aspects of administration including handling difficulties experienced during administration. Significantly more patients found the PEGASYS® pre-filled syringe more user-friendly than the pegylated interferon alfa-2b (12KD) injector (p=0.001). Janisch H-D, et al. 56th AASLD 2005; Abstract 1236 PEGASYS® – pre-filled syringe (n=56) Janisch H-D, et al. 56th AASLD 2005; Abstract 1236

患者依从性对SVR率的重要影响 ——利巴韦林累积暴露剂量 完成治疗的基因1型患者 EOT率 SVR率 复发率 P= 0.0006 90 80 70 60 50 40 30 20 10 总体 n=427 > 97 % >80-97 % > 60-80 % 0-60 % Reddy KR et al Clin Gastroenterol Hepatol 2007

派罗欣在各个方面都具有显著的优势 卓越设计 非凡高效 更好 的疗效 分布容积更低 相对固定剂量 便于临床治疗 更低的峰谷比 良好的耐受性 更好的依从性 半衰期更长 持久病毒抑制 防止病毒反弹 稳定的分子键 以溶液形式存在 方便用药 更好 的疗效

聚乙二醇干扰素α-2a与聚乙二醇干扰素α-2b的“头对头”对比研究 Slide 33. Randomised controlled studies Data are available from three randomised head-to-head studies that have compared PEGASYS® plus COPEGUS® combination therapy with pegylated interferon alfa-2b (12KD) plus ribavirin combination therapy

病例3： 患者，男性，45岁，10年前输血感染丙肝，治疗前检查：肝功能112IU/L，HCV RNA 8×10*6拷贝/毫升，基因分型为基因1型，血常规白细胞、血红蛋白均、甲状腺功能均正常。 治疗前医生为患者介绍了两种聚乙二醇干扰素的治疗方案，并详细解释了二者的优劣，最终为患者选择了聚乙二醇干扰素α-2a180ug每周联合利巴韦林1200mg/天的联合治疗方案。

问题3： 医生是基于哪些理由为患者选择了聚乙二醇干扰素α-2a？ 聚乙二醇干扰素α-2a每周注射一次，且剂量固定，使用更方便，依从性更高， 在利巴韦林起始剂量和减量方案相同时，聚乙二醇干扰素α-2a的疗效优于聚乙二醇干扰素α-2b 回顾性研究表明，在相同的累积利巴韦林剂量组，聚乙二醇干扰素α-2a的疗效优于聚乙二醇干扰素α-2b 以上都是

派罗欣®与聚乙二醇干扰素α-2b(12KD) 之间的“头对头”研究 Study Design Country n Genotype SVR PEGASYS SVR Pegintron p Ascione et al.1 RCT Italy 320 All 68.7% 54.4 0.008 MIST2 431 66% 54% 0.02 IDEAL3 USA 3070 G1 41% 40% NS PRACTICE4 Retrospective Germany 1696 59.3% 53% US Vetarans Affairs study5 5944 31% 24% <0.001 Slide 3. Comparison of PEGASYS versus pegylated interferon alfa-2b (12KD) head-to-head studies From this overview of the head-to-head data available for PEGASYS versus pegylated interferon alfa-2b (12KD) it is clear that PEGASY has consistently higher SVR rates Ascione A, et al. J Hepatol 2008; 48(Suppl 2): S370 Rumi M, et al. Hepatology. 2008; 48(4 Suppl): 404A Sulkowski M, et al. J Hepatol. 2008; 48 (Suppl 2): S370-1 Craxi A, et al. J Hepatol 2008; 48 (Suppl 2): S291 Witthoeft T, et al. J Hepatol. 2008; 48 (Suppl 2): S315 Backus LI, et al. Hepatology 2007; 46: 37-47 RCT=randomised controlled trial 1. Ascione A, et al. J Hepatol 2008; 48(Suppl 2): S370 2. Rumi M, et al. Hepatology. 2008; 48(4 Suppl): 404A 3. Sulkowski M, et al. J Hepatol. 2008; 48 (Suppl 2): S370-1; 4. Witthoeft T, et al. J Hepatol. 2008; 48 (Suppl 2): S315; 5. Backus LI, et al. Hepatology 2007; 46: 37-47

Ascione研究：头对头研究 随机, 对照, 开放, 单中心, 研究者发起的临床研究 研究对象：初次治疗的丙肝患者 所有患者按基因分型分层 利巴韦林起始剂量和剂量调整方案完全一致 初级研究终点: 疗效 Slide 5. Ascione (Neapolitan) head-to-head study Ascione and colleagues conducted a randomised, open-label, comparative study in Naples. Patients with chronic hepatitis C of all genotypes were eligible. Patients with cirrhosis were also eligible, provided they had compensated liver disease. Ascione A, et al. J Hepatol. 2008; 48(Suppl 2): S370. Abstract 990 Ascione A, et al. J Hepatol 2008; 48(Suppl 2): S370

聚乙二醇干扰素α-2b (12KD) 1.5 g/kg/wk 联合利巴韦林 1000/1200 mg/天 Ascione研究：设计 聚乙二醇干扰素α-2b (12KD) 1.5 g/kg/wk 联合利巴韦林 1000/1200 mg/天 随访 患者 派罗欣® 180 g/周 联合 利巴韦林 1000/1200 mg/天 随访 Slide 6. Ascione study: design 320 eligible patients were randomised to treatment with PEGASYS® 180 µg once weekly plus ribavirin or, PegIntron 1.5 µg/kg/week plus ribavirin. The ribavirin dosage regimen was identical in the two arms of the study (1000 mg if <75 kg, 1200 mg if ≥75 kg). The duration of treatment was that recommended in treatment guidelines: 48 weeks in genotype 1 or 4 patients (as shown by the arrow in the figure) and 24 weeks for those infected with genotypes 2 or 3 (as shown by the arrow in the figure). The use of growth factors (ESAs) was not allowed for the management of anaemia. The primary efficacy end-point was SVR defined as undetectable HCV RNA (Cobas Amplicor™ HCV Monitor Test v2.0, limit of detection 50 IU/mL) after 24 weeks of untreated follow-up. Ascione A, et al. J Hepatol. 2008; 48(Suppl 2): S370. Abstract 990. 24 周 48 72 基因2/3型 基因¼型 随机分组 Ascione A, et al. J Hepatol 2008; 48(Suppl 2): S370

Ascione研究: 派罗欣®可以获得更高的SVR率 PEGASYS® Peg-IFN-2b (12KD) p=0.046 100 88 90 p=0.008 p=0.002 80 75 69 p=0.04 69 70 60 54 55 SVR (%) 46 50 40 40 30 Slide 8. Ascione study: higher SVR rates achieved with PEGASYS® than with pegylated interferon alfa-2b (12KD) The primary endpoint for the study was efficacy (SVR). Treatment with the combination of PEGASYS® plus ribavirin produced consistently significantly higher SVR rates compared with PegIntron plus ribavirin overall in the two genotype subgroups (1 and 4, and 2 and 3) and in patients with high baseline viral loads (defined as >500,000 IU/mL in this study) (ITT results). The protocol specified that all patients infected with HCV genotypes 1 or 4 were assigned to 48 weeks of treatment and all patients infected with HCV genotypes 2 or 3 were assigned to 24 weeks of treatment. (All but 3 genotype 2 patients were assigned to 24 weeks of treatment). Ascione A, et al. J Hepatol. 2008; 48(Suppl 2): S370. Abstract 990 20 10 Overall Genotype 1/4 Genotype 2/3 HVL (>500,000 IU/mL) HVL = high viral load Ascione A, et al. J Hepatol 2008; 48(Suppl 2): S370

Ascione研究: 派罗欣®的复发率更低 PEGASYS® Peg-IFN-2b (12KD) 100 90 80 70 60 Relapse (%) 50 40 p=0.04 p=0.18 30 p=0.41 20 Slide 9. Ascione study: relapse rates with PEGASYS® and pegylated interferon alfa-2b (12KD) Similar overall relapse rates were observed with PEGASYS® and pegylated interferon alfa-2b (12KD). Ascione A, et al. J Hepatol. 2008; 48(Suppl 2): S370. Abstract 990 20 15 10 10 10 10 8 Overall Genotype 1/4 Genotype 2/3 Ascione A, et al. J Hepatol 2008; 48(Suppl 2): S370

Ascione研究: 是否使用派罗欣®是SVR的独立预测因素(MLR analysis) 多因素回归分析 P-value 4.83; 2.81–8.31 基因 2/3型 0.000 2.36; 1.27–4.41 慢性活动性肝炎 0.007 2.32; 1.39–3.88 派罗欣治疗 0.001 1.93; 1.17–3.20 Slide 10. Ascione study: treatment with PEGASYS® is a predictor of SVR (MLR analysis) In an MLR analysis treatment with PEGASYS® was shown to be a significant predictor of SVR(p<0.001). Ascione A, et al. J Hepatol. 2008; 48(Suppl 2): S370. Abstract 990 男性 0.011 0.5 1 10 获得 SVR的可能性更低 获得SVR的可能性更高 Odds ratio (95% 可信区间) Ascione A, et al. J Hepatol 2008; 48(Suppl 2): S370

Ascione研究: 派罗欣®组由于不良反应退出研究者更少 由于不良反应退出研究的比例: 派罗欣®: 4/160 (2.5%) 聚乙二醇干扰素α-2b(12KD): 17/160 (10.6%) Slide 11. Ascione study: fewer withdrawals due to adverse events with PEGASYS® In the comparative study by Ascione et al. presented at EASL 2008 only 4 patients discontinued treatment in the group treated with PEGASYS® compared with 17 of those randomised to pegylated interferon alfa-2b (12KD). Ascione A, et al. J Hepatol. 2008; 48(Suppl 2): S370. Abstract 990 Ascione A, et al. J Hepatol 2008; 48(Suppl 2): S370

PRACTICE研究背景 回顾性数据收集 派罗欣或聚乙二醇干扰素α-2b+RBV治疗 从2000至2007 (完成治疗) 在23个参与研究的德国HCV治疗中心，各地派罗欣 + RBV与聚乙二醇干扰素α-2b + RBV的疗效和安全性具有可比性 Witthoeft et al, EASL 2008

PRACTICE研究设计 通过两种配对分析方法进行ITT分析: 1) 配对标准1 (MP1): 各组患者基线特征相同， 难治性患者比例高 在配对标准1的基础上，对患者按照利巴韦林累积剂量进行配对≤60%；>60～≤80%；>80～≤100%；>100% Witthoeft et al, EASL 2008

PRACTICE研究： 所有配对分析中派罗欣组的SVR率均显著优于聚乙二醇干扰素α-2b组 派罗欣+利巴韦林 聚乙二醇干扰素α-2b+利巴韦林 65 p=0.04 p=0.008 59.9 59.3 60 SVR (%) 55.8 55 53.0 50 配对I 配对II Witthoeft et al, EASL 2008

PRACTICE研究结论 在此项设计严谨的大样本、队列对照研究中 ，SVR的阳性预测因子包括：采用派罗欣治疗、低病毒载量（<400,000IU/ml）、基因2/3型 Witthoeft et al, EASL 2008

临床实践中的对比研究 临床实际治疗考验药物的真正疗效 临床实践中的对比研究 临床实际治疗考验药物的真正疗效 Slide 23. Real world cohort studies

临床研究和实际治疗的患者情况存在差异 患者基线情况 年龄、体重、合并症、精神状态、基因型、毒品史、治疗史 各种情况的患者都有，可能有较高比例的难治型患者 严格的纳入 和排除标准 临床研究 实际治疗

临床研究和实际治疗的患者情况存在差异 治疗过程 医药 公司 患者 医务 人员 门诊治疗 按医保规定购药 依从性较差 依从性更好 药品资助 患者 医务 人员 由于经济原因、不良事件而自行减量、停药 更多关注、管理、监控、随访 依从性较差 规范治疗的比例较低 依从性更好 治疗更规范 临床研究 实际治疗

派罗欣+利巴韦林治疗方案： 国际多中心临床试验均呈现理想的SVR率 2002年Fried研究 SVR=56% 2004年Hadziyannis研究 SVR=63% 2006年Zeuzem研究 SVR=66% 1. Fried MW et al. N Engl J Med. 2002; 347(13): 975-82; 2. Hadziyannis S, et al. Ann Intern Med 2004; 140: 346; 3. Zeuzem S, et al. J Hepatol 2005; 43: 250.

派罗欣联合治疗方案： 临床试验和实际治疗中始终一贯的卓越疗效 真实的临床数据 派罗欣180 g+利巴韦林* 德国3 Practice研究5 临床试验中的SVR率1, 2 法国4 100 90 84% 85% 79% 80 76% 73% 70 66% 63% 60% 61% 60% 60 52% SVR (%) 49% 50 40 30 20 10 总体 基因1型 基因2/3型 * 利巴韦林的推荐剂量：基因1型是1000–1200 mg/天；基因2/3型是800 mg/天. 1. Zeuzem S, et al. J Hepatol 2005; 43: 250; 2. Hadziyannis S, et al. Ann Intern Med 2004; 140: 346; 3. Zehnter E, et al. 56th AASLD 2005; Abstract 1233; 4. Bourliere M, et al, AASLD 2007; Abstract 285; 5. Witthoeft T, et al. EASL 2008; 6. Deschénes et al, EASL 2007.

Peg-IFN-2b (12KD)： III期临床和实际治疗的SVR率均不够理想 Peg-IFN-2b (12KD) 1.5 g/kg +利巴韦林* 真实的临床数据 Manns III期临床试验1 WIN-R2 POWeR3 100 90 82% 80 75% 70 62% 60 54% 54% SVR (%) 50 44% 42% 42% 40 34% 30 20 10 n= 504 2121 738 348 1313 1078 351 808 665 总体 基因1型 基因2/3型 * 利巴韦林剂量: Manns研究=800 mg/天; WIN-R研究=800-1400 mg/天; POWeR研究=800-1200 mg/天。 1. Manns MP, et al. Lancet. 2001; 358(9286): 958-65; 2. Jacobson, AASLD 2005; 3. Marotta et al, AASLD 2007, Abstract 25.。

派罗欣：未来丙肝治疗方案的基础用药 酶抑制剂 利巴韦林 免疫调节剂 ± ± 派罗欣将作为未来丙肝联合治疗方案的平台

谢 谢!