美罗华注射液

2006 10 13 2007 05 10 2007 11 12 2008 06 03 2008 11 14 2009 03 09 2009 06 17 2009 07 30 2010 02 26 2010 05 21 2011 03 30 2012 01 04 2012 04 12 2012 05 17 2012 08 24 2013 07 11 2013 10 16 MabThera Rituximab Injection Lituoxi Dankang Zhusheye 1 40

80 B C D B CD20 III-IV CVP 8 CD20 B DLBCL CHOP 8 100 /10 500 /50 0.9% 5% 1mg/ml 24 2 40

X 375 mg/m 2 BSA 22 4 CVP 375 mg/m 2 BSA 8 21 1 375 mg/m 2 BSA 4 1 4 B CHOP 375mg/m 2 BSA 50 mg/h 60 30 50 mg/h 400 mg/h 100 mg/h30 100 mg/h 400 3 40

ADRs 2% 1/10 1/100--<1/10 1/1000--<1/100 / 1 356 671 R-CHOP R-CVP R-FCM 2 12 1 1. N=356 N=671 10% 1 % - < 10% 0.1%- < 1% + + + + LDH 4 40

+ + + + + + + + + IgG + 3 NCI NHL CLL 2 / / 202 R-CHOP DLBLC 234 162 R-CHOP R-CVP 397 CLL 274 / CLL R-FC 2. R-CHOP DLBCL N=202 N=234 R-CVP N=162 R-FC CLL N 397 / CLL N 274 10% % 1- <10% 5 40

* # * R-FC/ CLL 3 NCI # / / R-FC <2% MCP CHVP-IFN CVP CHOP FC -4 50% NHL R-CVP DLBCL R-CHOP CLL R-FC 12% 1% 6 40

90 f-nhl R-CVP DLBCL R-CHOP 90 U4391g 363 90 2 / 3-4 1.1% 95 % CI [0.3%, 2.8%] 90 2-8 3-4 2.8% 95%CI [1.3%, 5.0%] -4 70% 80 % B 356 30.3% 3.9% 3/ 4 2 NHL / 3-4 2 NHL R-CVP DLBCL R-CHOP CLL R-FC -CVP 12.3% CVP 16.4% R-CVP 4.3% CVP 4.4% R-CHOP R-CHOP 2-4 45.5% CHOP 42.3% R-CHOP 2-4 R -CHOP 4.5% vs CHOP 2.6% R-CHOP 2-4 4.5 % CHOP 1.5 % 2-4 / R-CHOP 55.4% CHOP 51.5% CLL 3 4 R-FC FC 7 40

2% 0% -4 4.2% 3 4 1.1% 1.7 % 2 NHL 3-4 2% vs 5% 4% vs 10% 3-4 1% vs <1 % / B B 12 NHL R-CVP DLBCL R-CHOP CLL R-FC 3/4 R -CHOP 88% CHOP 79% R-FC 23% FC 12% ( R-CVP 24% CVP 14% R-CHOP 97% CHOP 88%, R-FC 30% FC 19%) / FC 3-4 CLL 4% R-FC 7% FC 3/4 7% R-FC 10% FC 3/4 / CLL R-FC 3/4 12% FC 13% R -FC 3/4 11% FC 9% -4 18.8% 3 4 8 40

2 NHL 3-4 <1 % 3% % 1 1 % <1 <1% NHL R-CVP DLBCL R-CHOP CLL R-FC R-CHOP R-CHOP 6.9% 3-4 CHOP 1.5 % /, 3 4 R-CHOP CHOP CLL 3 4 R-FC 4% FC 3% / R-FC 4% FC 4% IgG 2 NHL IgG < 7g/L IgG 2 IgG 60% 2 36% NHL R-CVP DLBCL R-CHOP CLL R-FC R-CHOP 2% CHOP 1.5% CLL 34 R-FC4% FC4% / R-FC3% FC3% -4 65 88.3% 92.0% 3 4 16.0% 9 40

18.1% 65 CLL / CLL 65 3/4 3 4 25.6%vs 15.4% 92.3%vs 89.2% 95.0%vs 89.7% 3 4 13.3% vs 14.8% / 3000 1 6 5 7198 2300 2 3 4 / 2 1000mg 2 500mg 2 10-25mg/ 3 2% 3 1/10 1/100 <1/10 1/1,000 < 1/100 3 10 40

* / /./ 2 % * 6 / 3095 / 1077 35 % 1 CTC1 2 / RA 1% 14/3095 CTC 4 CTC 3 3 3095 720 23% / 11 40

/ 97/100 4/100 3 1.9% / 0.8/100 GPA MPA GPA MPA 99 / 375 mg/m2, 4 4 / 10% 4 1/10 4. 6 / GPA MPA 10% * n =99 a 61 (61.6%) 46 (46.9%) 18 (18.2%) 20 (20.4%) 17 (17.2%) 12 (12.2%) 17 (17.2%) 19 (19.4%) 17 (17.2%) 13 (13.1%) 15 (15.3%) 9 (9.2%) 16 (16.2%) 10 (10.1%) 20 (20.4%) 26 (26.5%) 16 (16.2%) 6 (6.1%) 13 (13.1%) 21 (21.4%) n = 98 12 40

n =99 n = 98 14 (14.1%) 12 (12.2%) ALT13 (13.1%) 15 (15.3%) 13 (13.1%) 11 (11.1%) 10 (10.1%) 11 (11.2%) 6 (6.1%) 11 (11.2%) 12 (12.1%) 5 (5.1%) b 12 (12.1%) 11 (11.2%) 10 (10.1%) 17 (17.3%) * 13 6 a b GPA MPA 24 99 / 12% CTC 1 2 / 99 / 210 100 (95% CI 173-256) 25 100 / 4% / 2.05 100 GPA MPA 13 40

RA IgG IgM IgG IgM RA 0.94% 13/1382 0.27% 2/731 3 4 1.06 0.53/100 0.97 0.88/100 GPA MPA /Rituxan GPA MPA IgA IgG IgM RTX 6 27% 58% 51% IgA IgG IgM CYC 25% 50% 46% IgA IgG IgM GPA MPA 24% 23% CTC 3 GPA MPA B 63 CD20 B 14 40

32 31 + CHOP CHOP 6 21 1 375mg/m 2 BSA 51.6% 50.0% 25% 20% 1 4 NCIC CTC / / - PRESRPLS 15 40

PRES/RPLS PRES/RPLS / CMV - JC PML Kaposi s Kaposi s HIV RA GPA MPA / RA GPA / MPA PML 16 40

IgM IgM 4 g CD4 CD8 NYHA IV 17 40

/ / 30 2 >25 10 9 /L CLL 50% 100 mg/h 50 mg/h >25 10 9 /L CLL 25 10 9 /L / 18 40

X- 1 2 CD20 TLS LDH >25 10 9 /L CLL TLS / 12 <1.5 10 9 /L / <75 10 9 /L CHOP CVP 19 40

HBV PML PML -, ( ) NHL 16% vs 81% 4% vs 76% 2 A 6 20 40

RA GPA MPA GPA MPA / / / RA RA / 1% 50% 100 mg/h 50 mg/h GPA MPA RA GPA MPA / 21 40

12 / Rituxan B CD4 CD8 / RA GPA MPA - PML PML PML 22 40

B RA 4 vs 42% 43% vs 82% KLH 34% vs 80% 6 4 RA MTX RA : : IgG. 23 40

B B B 12 IgG B HAMA HACA 24 40

373 DMARD 240 DMARD DMARD 6.1/100, DMARD 4.9/100 1000mg 5g B 166 375mg/m 2 BSA 4 48% CI 95% 41%-56% 6% 42% 13.0 IWF B C D ORR IWF A 58 % vs 12% 5cm 7cm 53%vs 38% 3 50% vs 22% 78% 43% LDH Fisher 25 40

40% 59% p=0.0186 logistic logistic bcl-2 8 37 B 375mg/m 2 BSA 8 57% CI 95% 41% -73% CR 14% PR 43% 19.4 5.3-38.9 4 39 375mg/m 2 BSA 4 36% CI 95% 21%-51% CR 3% PR 33% 9.6 4.5-26.8 4 58 B 375mg/m 2 BSA 4 60 38% CI 95% 26%-51% CR 10% PR 28% 17.8 5.4-26.6 12.4 CVP 322 B CVP 750 mg/m 2 1.4 mg/m 2 1 2 mg 1 5 40 mg/m 2 / 3 8 375 mg/m 2 BSA CVP R-CVP 26 40

321 162 R -CVP 159 CVP 53 R-CVP CVP 25.9 vs 6.7 p 0.0001 long -rank CR Cru PR R-CVP 80.9% CVP 57.2% R-CVP 33.6 CVP 14.7 p 0.0001 long-rank R-CVP 37.7 CVP 13.5 p 0.0001 longrank long-rank 53 R-CVP 80.9% vs CVP 71.1% 42 R-CVP CVP 5 5. CVP vs R-CVP 42 Kaplan-Meier CVP R-CVP ( 41.3 42.1 Log-Rank p 6.6 27.0 <0.0001 66% 14.5 33.6 <0.0001 58% NR NR 0.0700 38% + CR Cru PR * 57% 81% <0.0001 ** 3.2 *** 13.5 37.7 <0.0001 65% 20.5 44.8 0.0005 71% 12.3 46.3 <0.0001 63% + G * ** *** CR CRu NR Kaplan-Meier 50% PR 27 40

R-CVP CVP p=0.02 log-rank R-CVP 3 93% CVP 85% M39021 BNLI vs 60 > 60 0-1 vs >1 vs LDH b 2 - B < 5 vs 5 12 g/dl vs >12 g/dlipi 1 vs > 1 FLIPI index 20-vs 3-5 III 465 / 6 CHOP N=231 CHOP R -CHOP N=234 334 N=167 N=167 3 375mg/m 2 BSA 2 31 R-CHOP CHOP / 6 6 CHOP R-CHOP 31 CHOP R-CHOP p 1 2 74% 87% 0.0003 2 16% 29% 0.0005 2 58% 58% 0.9449 0.0508 32% 19.4 33.2 0.0001 38% 1 2 / p<0.0001 28 PFS p <0.0001 log-rank 28 40

PFS 42.2 14.3 Cox 61% CI 95% 45%-72% 12 Kaplan- Meier PFS 78% 57% p=0.0039 log-rank 56% C I 95% 22% -75% 38.8 vs 20.1 p<0.0001 log-rank 50% CI 95% 30%-64% CR CRu DFS53.7 vs 16.5 p=0.0003 log-rank 7 CR 67% CI 95% 39% -82% 7. vs 28 Kaplan-Meier N=167 N=167 log-rank p 14.3 42.2 <0.0001 61% 0.0039 56% 20.1 38.8 <0.0001 50% a 16.5 53.7 0.0003 67% CHOP 11.6 37.5 <0.0001 71% R-CHOP 22.1 51.9 0.0071 46% 14.3 52.8 0.0008 64% 14.3 37.8 <0.0001 54% CHOP 0.0348 55% R-CHOP 0.0482 56% a CHOP R-CHOP CR PR 8 CHOP PFS 37.5 11.6 p<0.0001 R-CHOP PFS 51.9 22.1 p=0.0071 PFS CHOP R-CHOP 29 40

60 >60 III IV WHO 0 vs >0B v s IPI 0-2 vs 3-5 FLIPI 0-1 vs 3-5 0-1 vs >1 < 5 vs 5 1 vs 2 CR/PR vs [NC]/ [PD] < 12g/dl vs 12g/dl b 2 - < 3mg/l vs 3mg/l LDH B 399 B 60 80 CHOP 750mg/m 2 50 mg/m 2 1.4 mg/m 2 2mg 1-5 40 mg/m 2 / 3 8 375 mg/m 2 CHOP R-CHOP CHOP=197 R-CHOP=202 31 R-CHOP p=0.0001 R-CHOP K-M 35 CHOP 13 41% 24 R-CHOP 68.2% CHOP 57.4% p=0.0071 60 R-CHOP CHOP R -CHOP 62.4% CHOP 50.8% p=0.0071 32% PFS DFS R-CHOP CHOP 8 R-CHOP CR 76.2% CHOP 62.4% p=0.0028 46% 51% IPI Ann Arbor ECOG β 2 LDH B R -CHOP vs CHOP 0.83 0.95 [IPI] R-CHOP 30 40

3 1 WA17042 517 III TNF ACR 24 ACR20 1000mg 15 100mg 1 10-25mg/ 2 7 60mg 8 14 30mg 24 56 X 2 WA17043 2 1000mg 2 500mg 3 3 II 1 5 DMARDs 3 WA 16291 DMARDs 3 10-25mg/ 3 2 1000mg ACR 20% 8 ACR HAQ C mg/d L 8. 24 ACR ITT ACR +MTX +MTX +MTX 1 1 WA17042 2 1000mg 2 500mg N=201 N=298 - RF- RF- 31 40

2 2 WA17043 3 WA16291 2 ACR20 ACR50 ACR70 ACR20 ACR50 ACR70 ACR20 ACR50 ACR70 36 18% 11 5 % 3 1% N=143 153 51% 3 80 27 % 3 37 12 % 3 RF- RF- RF- 45 31% 19 13 % 6 4% N=40 N=185 96 52% 4 61 33 % 4 28 15 % 4 N=40 RF- RF- 15 38% 5 13% 2 5% 28 70% 5 17 43 % 5 9 23% 5 - - - N=185 68 56% 4 40 33 % 4 16 13 % 4 - - - - 1 TNF 2 DMARDs 3 p 0.0001 4 p 0.001 5 p 0.05 RF= 3 ACR20 38% ACR20 65% p=0.025 DAS28 EULAR 9 9. 24 DAS EULAR ITT +MTX +MTX +MTX 2 1000mg 2 500mg 1 WA17042 1 N=201 N=298 - RF- RF- DAS28 [ -0.4 1.2 ] -1.9 1.6 * - EULAR % 78% 20% 2% 35% 50% 15% 2 WA17043 2 N=143 N=185 N=123 RF- RF- RF- DAS28 [ -0.8 1.4-2.0 1.6-1.9 1.4-32 40

] EULAR % 61% 35% 4% 37% 40% 23% 3 WA16291 2 N=201 N=298 - RF- RF- DAS28 [ -1.3 1.2 ] -2.6 1.3 - EULAR % 50% 45% 5% 18% 63% 20% 1 TNF 2 DMARDs 3 p 0.0001 4 p 0.001 5 p 0.05 RF= 28 59 14 - TNF 1 X Sharp -- 56 X 56 10 10. 1 56 X +MTX +MTX 2 1 000mg 1 n=184 n=273 Sharp 2.30 1.01 p=0.0046 1.32 0.60 p=0.0114 0.98 0.41 p=0.0006 56 52% 60% NS p=0.0494 33 40

HAQ-DI FACIT -F SF-36 11 12 HAQ-DI FACIT -F SF-36 11. SF-36 24 1 2 +MTX N=197 +MTX N=294 +MTX N=141 +MTX N=178 1.3 9.4 4.7 11.8 1.8 8.0 3.2 11.2 p- * 0.0002 40 20% 111 38% 29 21% 60 34% 128 65% 144 49% 99 70% 90 51% 29 15% 39 13% 13 9% 28 16% p- * 0.0015 0.9 5.7% 5.8 8.5% 1.96 6.3% 6.1 8.2% p- * <0.0001 25 13% 141 48% 37 26% 88 49% 158 80% 136 46% 92 65% 81 46% 14 7% 17 6% 12 9% 9 5% p- * <0.0001 * 2 > -6.33= -6.33 < 6.33= < -6.33= > -5.42= -5.42 < 5.42= < -5.42= 12. 1 WA17042 24 HAQ FACIT-F 24 +MTX 1 N=201 +MTX 1 p- N=298 HAQ 2-0.1 0.5-0.4 0.6 <0.0001 FACIT-F 3-0.5 9.8-9.1 11.3 <0.0001 1 2 HAQ 3 FACIT -F 34 40

3 24 HAQ-DI >0.25 10% HACA HACA HACA B 3 RF 45-64% 1. RF weeks 60 0 4 16 24 40 20 % change in RF 0-20 -40-60 -80 Rit+MTX (%change) MTX (%change) 4 24 IgG 35 40

3 6 C- A S100 A8 A9 RF 1 N- [P1NP] 24 P1NP 24 B 6-12, DAS28 2 2. DAS28 TNF 36 40

B 63 40-75 CD20 B 32 31 + CHOP CHOP 6 21 1 375mg/m 2 BSA CR29.0% PR54.9% 83.9% CR31.3% PR31.3% 62.5% CD20 CD20 B B B CD20 95% B CD20 CD20 CD20 B CD20 B B CDC ADCC B 6 12, B B / B 2 67 HAMA 356 HACA 4 1.1% B 37 40

298 CHOP NHL CL 1 B CL 2 V 1 0.14 L/day 0.59 L/day 2.7 L 22 6.1 52 161 375 mg/m 2 4 CD19 CL 2 CD-19 CL 2 CD-19 CL 2 BSA CHOP BSA1.53 2.32 m 2 CHOPV 1 27.1% 19.0% WHO 203 NHL 375 mg/m 2 4 4 C max 486 µg/ml 77.5 996.6 µg/ml CD-19 B IWF B C D A 3-6 37 NHL 375 mg/m 2 8 C max C max 243 µg/ml 16 582 µg/ml 550µg/mL 171-1177µg/mL 6 375 mg/m 2 6 CHOP 2 2 1000mg 20.8 8.58-35.9 0.23L/day 0.091-0.67L/day 4.6 L 1.7-7.51L 0.26 L/ 20.4 1 38 40

4 1 15 500 mg 1000 mg max 157 171 mg/ml 2 500 298 341mg/mL 2 1000mg 2 C max 183 198 mg/ml 2 500mg 355 404 mg/ml 2 1000mg 15 16.5 2 500mg 17 21 2 1000mg 1 2 max 16% 19% 2 2 500mg 1000mg max 170 175 mg/ml 2 500mg 317 370mg/mL 2 1000mg 2 C max 207mg/mL 2 500mg 377 386 mg/ml 2 1000mg 2 2 19 2 500 mg 21 22 2 1000 mg PK 2-8 12 2-8 24 100 /10 1 / 2 / 500 /50 1 / 30 39 40

JS20100063 100mg/10ml S20120002 S20120003 500mg/50ml S20120004 S20120005 100mg/10ml J20120019 500mg/50ml J20120020 Roche Pharma (Schweiz) Ltd. Schoenmattstrasse 2, CH-4153, Reinach, Switzerland Roche Diagnostics GmbH Sandhofer Strasse 116, 68305 Mannheim, Germany 1100 201203 021 28922888 021-50801159 021 50801800 800 820 8780 400-820-8780 9:00-17:00 MabThera http://www.roche.com.cn 40 40