0716-GAZ-01 GAZYVA Solution for Infusion obinutuzumab 000973 B (Progressive Multifocal Leukoencephalopathy; PML) B (HBV) CD20 (CD20-directed cytolytic antibodies)( GAZYVA) GAZYVA HBV GAZYVA HBV HBV GAZYVA [(5.1)] (PML) PML GAZYVA [(5.2)] 1. 1.1 chlorambucil (comorbidities) fludarabine CD20 (CLL) 1.2 bendamustine GAZYVA rituximab (FL) 2. 2.1 (pre-medication)[ (2.2)] (tumor lysis syndrome TLS) [ (2.2)(5.4)] [ (2.5)] (push) (bolus) GAZYVA [(5.3)] (CLL) GAZYVA 1000 mg 1 1 (100 mg) 2 (900 mg) 1 CLL 6 ( 28 ) GAZYVA GAZYVA ( / ) 1 1 100 mg 25 mg/hr 4 () 2 900 mg 50 mg/hr 1
30 50 mg/hr 400 mg/hr 8 1000 mg 15 1000 mg 100 mg/hr 100 mg/hr 30 2-6 1 1000 mg 100 mg/hr 400 mg/hr GAZYVA 1 1 1 2 (FL) GAZYVA 1000 mg 2 6 GAZYVA bendamustine (SD) (CR) (PR) GAZYVA 1000 mg 2 2 FL 6 ( 28 ) GAZYVA GAZYVA GAZYVA ( / ) 50 mg/hr 1 1000 mg 30 50 mg/hr 400 1 mg/hr () 8 1000 mg 15 1000 mg 2-6 1 1000 mg 2 2 1000 mg 100 mg/hr 100 mg/hr 30 100 mg/hr 400 mg/hr GAZYVA GAZYVA bendamustine CLL FL CLL FL [ (5.3)] 4 () GAZYVA 3 ( ) () 3 CLL 1 1 25 mg/hr 1-2 ( ) CLL 1 1 25 mg/hr 2.2 2
( 2 3) [(5.3)] GAZYVA GAZYVA 12 1 [(5.3)] (tumor lysis syndrome TLS) (high tumor burden)( 25 x 10 9 /L) TLS GAZYVA ( allopurinol rasburicase) GAZYVA [(5.4)] 3 GAZYVA (IRR) 1 CLL 1 2 FL 1 ( 1-2 ) 3 >25 x 10 9 /L 650-1000 mg acetaminophen ( 50 mg diphenhydramine) 1 hydrocortisone (glucocorticoid) 20 mg GAZYVA dexamethasone 80 mg 1 methylprednisolone 1 650-1000 mg acetaminophen GAZYVA ( 50 mg 30 diphenhydramine) 650-1000 mg GAZYVA acetaminophen 30 650-1000 mg acetaminophen GAZYVA ( 50 mg 30 diphenhydramine) GAZYVA 20 mg dexamethasone 80 mg methylprednisolone 1 1 GAZYVA 30 2.3 3-4 (neutropenia) 1 1 2 2.4 3 4 (cytopenia) 2 2.5 3
0.9(PVC)(non-PVC polyolefin) (5) (CLL) 1 1 (100 mg) 2 (900 mg) 40 ml GAZYVA 4 ml (100 mg) GAZYVA 100 ml 0.9 36 ml (900 mg) GAZYVA 250 ml 0.9 2 2 C 8 C 24 1 8 15 2-6 1 40 ml GAZYVA 40 ml (1000 mg) GAZYVA 250 ml 0.9 (FL) 40 ml GAZYVA 40 ml (1000 mg) GAZYVA 250 ml 0.9 GAZYVA 2 C 8 C 24 0.4 mg/ml 4 mg/ml CLL FL (push) (bolus) GAZYVA GAZYVA (PVC)(non-PVC polyolefin) [ / (14.1)] 3. 1000 mg/40 ml (25 mg/ml) 4. 5. 5.1 B B (HBV) CD20 ( GAZYVA) HBV B (HBsAg) HBsAg B (anti-hbc) B ( HBsAg anti-hbc B 4
[anti-hbs] ) HBV HBV HBV DNA HBsAg anti-hbc HBsAg HBV GAZYVA HBsAg anti-hbc HBV B (HBsAg [ ] HBsAg anti-hbc ) B HBV GAZYVA HBV HBV CD20 HBV GAZYVA HBV GAZYVA B HBV GAZYVA HBV GAZYVA 5.2 GAZYVA JC (PML) PML PML () (MRI) PML GAZYVA 5.3 GAZYVA 65 CLL GAZYVA 1000 mg 38 (inhl) 1 GAZYVA () [ (6.1)] acetaminophen ( / ) GAZYVA 24 [ (2)] 4 ( [anaphylaxis] ) GAZYVA GAZYVA 1 2 3 3 GAZYVA 1 2 [ (2)] GAZYVA GAZYVA 12 (hypertensive crisis) 5
5.4 GAZYVA (TLS) (>25 x 10 9 /L) TLS TLS GAZYVA ( allopurinol rasburicase) [ (2.2)] GAZYVA TLS TLS 5.5 GAZYVA GAZYVA GAZYVA 5.6 GAZYVA 3 4 3 4 (G-CSF) ( 28 ) / ( 28 ) 3 4 (>1 ) 1 2 5.7 GAZYVA chlorambucil bendamustine GAZYVA CLL 1 1 3 4 GAZYVA ( ) ( ) 1 5.8 GAZYVA B 6. B [(5.1)] [(5.2)] [(5.3)] [(5.4)] 6
[(5.5)] [(5.6)] [(5.7)] 6.1 CLL 4 5 773 CLL chlorambucil GAZYVA chlorambucil rituximab chlorambucil 1 GAZYVA chlorambucil chlorambucil 2 GAZYVA chlorambucil rituximab chlorambucil 2 1 2 GAZYVA 1 (5 vs. 2) (12 vs. 10) (10 vs. 7) 3 4 (<1 vs. 0) (0 vs. <1) (5 vs. 4) GAZYVA 1 (33 vs. 18) (30 vs. 20)(18 vs. 11) 3 4 1 GAZYVA 1000 mg 5 28 1000 mg chlorambucil ( 6 28 ) 140 1 GAZYVA 1 (100 mg) 2 (900 mg) [ (2.1)] 81 6 ( 28 ) GAZYVA GAZYVA CLL ( 10) GAZYVA CLL 3-4 ( 10) 4 CLL 5 GAZYVA 2 ( 2 ) GAZYVA + Chlorambucil n = 336 Rituximab + Chlorambucil n = 321 3-4 3-4 66 20 38 4 a 38 33 32 28 14 10 7 3 6 4 2 <1 9 <1 7 <1 7
10 2 8 <1 8 0 5 0 6 <1 3 0 5 1 2 <1 a 5 CTCAE CLL 5 GAZYVA 2 ( 2 ) GAZYVA + Chlorambucil n = 336 Rituximab + Chlorambucil n = 321 3-4 3-4 76 46 69 41 80 39 50 16 84 35 62 16 48 13 40 8 39 10 37 10 37 3 32 <1 14 1 10 <1 26 7 18 2 AST / GOT 27 2 21 <1 ALT / GPT 28 2 21 1 23 <1 16 <1 (NHL) GAZYVA 392 (inhl) 81 (FL) FL inhl GAZYVA bendamustine (G+B) GAZYVA bendamustine (B) G+B 1 GAZYVA 1000 mg 5 28 1000 mg 6 1 2 bendamustine 90 mg/m 2 B 1 2 bendamustine 120 mg/m 2 6 28 G+B 2 GAZYVA 1000 mg 2 G+B 79 6 GAZYVA 76 6 bendamustine B 67 6 bendamustine GAZYVA inhl ( 10) 8
GAZYVA inhl 3-4 ( 10) 6 inhl 5 G+B GAZYVA 2 GAZYVA+Bendamustine GAZYVA Bendamustine n = 194 n = 198 3-4 3-4 a 69 11 63 6 35 33 28 26 19 0 16 0 5 0 3 0 18 1 14 0 11 1 8 0 13 2 8 1 12 1 5 0 10 3 6 0 9 0 4 0 12 0 5 0 9 1 4 0 26 0 17 0 7 0 2 0 9 0 6 0 a 24 GAZYVA inhl (15) (12) (11)(10) (8) (8) (8) (8) (7)(7) (6)(6) (6) 3-4 (10) ( 1) 7 CTCAE inhl 5 G+B GAZYVA 2 a 9
GAZYVA+Bendamustine GAZYVA n = 194 3-4 Bendamustine n = 198 3-4 75 52 77 42 86 47 88 34 99 93 99 85 38 2 26 2 41 7 38 7 ALT/ GPT 35 1 31 4 87 4 92 2 ( ) 58 6 61 4 a 3-4 2 GAZYVA (80) (63) (50) (46) 3-4 (52) (27) (20) GAZYVA (69) (43) (25) AST/ GOT (24) ALT/ GPT (21) 3-4 (5) (3) (CLL) GAZYVA 65 3 4 20 7 1000 mg 3<1 1000 mg 3 4 GAZYVA 53 47 (89) acetaminophen ( 1 100 mg 2 900 mg) 140 74 (53) 1000 mg ( 1 64 2 3 7 ) <3[ (2)] (NHL) 69 G+B () 3-4 11 1 G+B () 55 3-4 9 G+B 1 (38) 2 8 15 ( 25 7 4) 2 G+B 24 GAZYVA () 8 3-4 2 GAZYVA 10
(CLL) GAZYVA rituximab 38 32 1 <1 ( 4) ( 28 ) GAZYVA 16 rituximab 12 (NHL) G+B (38) B (32) G+B (3) (7) (CLL) GAZYVA rituximab GAZYVA rituximab 38 37 3-4 11 13 1 (NHL) G+B 66 B 56 3-4 16 14 G+B 3 B 4 (CLL) GAZYVA (14) rituximab (7) 3-4 10 3 ( 4) 1 1 () GAZYVA rituximab 11 3 3-4 8 2 GAZYVA 4 ( GAZYVA 24 ) Rituximab 3 GAZYVA 4 GAZYVA 1 (NHL) G+B (15) B (24) G+B 11 B 10 3-4 (G+B 5 B 3) CLL GAZYVA 3 4 2 inhl G+B 0.5 (CLL) ( ) GAZYVA rituximab (18 15) (NHL) ( ) G+B 11
B (41 29) CLL (AST ALT ) GAZYVA 24-48 CLL (GAZYVA 4 )( acetaminophen) 1 GAZYVA NHL 6.2 (Immunogenicity) CLL GAZYVA CLL GAZYVA 7 (18/271) GAZYVA inhl G+B 194 2 (1) GAZYVA GAZYVA inhl GAZYVA GAZYVA GAZYVA GAZYVA 6.3 GAZYVA 7. GAZYVA 8. 8.1 GAZYVA B [ (11.1)] GAZYVA 20 obinutuzumab ( ) 1000 mg 2.4 [ ] GAZYVA 2-4 15-20 / 12
GAZYVA B [ ] GAZYVA B [(5.8) (11.2)] 20 ( ) obinutuzumab 25 50 mg/kg (AUC) CLL 2.4 28 obinutuzumab B 6 B 20 obinutuzumab 28 obinutuzumab 25 50 mg/kg 0.04 0.13 8.2 GAZYVA obinutuzumab [(8.1)] IgG GAZYVA GAZYVA 8.3 GAZYVA 8.4 (CLL) GAZYVA chlorambucil 336 CLL 81 65 46 75 75 467 <75 332 [ (13.1)] (NHL) GAZYVA bendamustine 194 inhl 44 65 14 75 65 5226 <65 2812 8.5 (CrCl) 30 ml/min GAZYVA GAZYVA CrCl <30 ml/min [ (11.3)] 8.6 GAZYVA 13
9. 50 mg 2000 mg GAZYVA 10. GAZYVA (obinutuzumab) IgG1 CD20 B CD20 150 kda GAZYVA (CHO) CHO IgG1 GAZYVA GAZYVA GAZYVA 1000 mg ( 25 mg/ml) L-histidine/L-histidine hydrochloride monohydrate trehalose dihydrate poloxamer 188 water for injection ph 6.0 11. 11.1 Obinutuzumab B B CD20 CD20 obinutuzumab (1) (2) ( ) / (3) B (ADCC)(ADCP) (fucose) rituximab obinutuzumab ADCC Obinutuzumab rituximab rituximab obinutuzumab FcγRIII CD20 obinutuzumab rituximab 11.2 CLL GAZYVA CD19 B ( CD19 B < 0.07 x 10 9 /L) GAZYVA 9 CD19 B 18 B B B B GAZYVA QTc 11.3 Obinutuzumab GAZYVA (TMDD) TMDD CLL obinutuzumab TMDD (CV) 4.1 (20) L, 0.11 (53) L/day 26.4 (48) inhl obinutuzumab TMDD (CV) 4.3 (22) L, 0.08 (45) L/day 36.8 (40) GAZYVA 14
(CrCl) 30 ml/min GAZYVA GAZYVA CrCl <30 ml/min GAZYVA 12. 12.1 Obinutuzumab 26 13. 13.1 (CLL) 781 ( (CrCl) <70 ml/min) CD20 CLL GAZYVA ( 1 BO21004 CLL11) CrCl <30 ml/min B (HBsAg anti-hbc anti-hbc B DNA ) C 28 chlorambucil ( 1 ) GAZYVA chlorambucil ( 2 ) rituximab chlorambucil ( 3 ) 356 1 1 2 663 2 2 3 GAZYVA 1 1 8 15 GAZYVA 1000 mg 5 ( 6 28 ) 140 GAZYVA 1 (100 mg) 2 (900 mg) [ (2.1)]( 1 6 ) 1 15 chlorambucil 0.5 mg/kg 1 73 62 95 65 CrCl <70 ml/min 76 22 Binet A 42 B 36 C CrCl 62 ml/min GAZYVA chlorambucil 81 6 rituximab 89 chlorambucil 67 1 1 (PFS) GAZYVA chlorambucil 27.2 chlorambucil 11.2 ( 22.8 ) PFS (OS) 46 22 (9) GAZYVA chlorambucil 24 (20) chlorambucil (hazard ratio) 0.41 (95 0.23-0.74) 1 2 PFS GAZYVA 26.7 rituximab 14.9 18.7 ( 0.42 95 0.33-0.54 p <0.0001) PFS (minimal residual disease, MRD) (ASO-PCR) 10 4 1 CLL ( MRD <10-4 ) (CR) (CRi) (GAZYVA 94 15
rituximab 34 ) GAZYVA rituximab 18 (19) 2 (6) MRD CR CRi GAZYVA rituximab 39 (41) 4 (12) 3 MRD 8 1 2 1a OS 2 PFS Kaplan-Meier 8 1 1 1 1 2 GAZYVA + GAZYVA + Rituximab + Chlorambucil* Chlorambucil Chlorambucil* Chlorambucil n = 238 n = 118 n = 333 n = 330 (PFS) 27.2 11.2 26.7 14.9 a ( 0.19 [0.14; 0.27] p <0.0001 ) ( 0.42 [0.33; 0.54] p <0.0001 ) (ORR) b 78.2 33.1 79.6 66.3 (CR) 28.2 0 26.1 8.8 2.5 1.7 2.1 1.5 (CRi) (PR) 45.0 30.5 48.6 54.1 (npr) 2.5 0.8 2.7 1.8 22.4 4.7 19.6 9.7 (OS) 0.41 [0.23; 0.74] a PFS b (ORR = CR + CRi + PR + npr) * 1 GAZYVA (n = 238) 2 GAZYVA (n = 333) 1 1 CLL Kaplan-Meier ( 1 ) Clb: Chlorambucil G-Clb: GAZYVA + Chlorambucil CI NR 16
2 1 CLL Kaplan-Meier ( 2 ) R-Clb: Rituximab + Chlorambucil G-Clb: GAZYVA + Chlorambucil CI PFS 13.2 (FL) 2 ( GAO4753g GADOLIN) rituximab rituximab 6 321 (FL) bendamustine (B) (n=166) GAZYVA bendamustine (G+B) (n=155) 6 28 6 G+B [ (CR) (PR) (SD)] GAZYVA 2 rituximab ( rituximab vs. rituximab ) ( 2 vs. >2 ) GAZYVA 1000 mg 1 1 8 15 2-6 1 2 2 bendamustine GAZYVA 90 mg/m 2 (1-6) 1 2 bendamustine 120 mg/m 2 2 63 88 5634 (Bulky disease)(>6 cm) 15 1 (B-symptom) 95 ECOG 0-1 3 2 ( 1 10) 46 1 33 2 20 rituximab 37 rituximab 41 rituximab rituximab rituximab (alkylating agent) 17
(double refractory) 79 2 (IRC) (PFS) 21.1 B PFS 13.8 G+B PFS ( 0.48 95 0.34-0.68 p <0.0001) PFS IRC PFS B PFS 13.7 G+B PFS 29.2 ( 0.48 95 0.35-0.67 p <0.0001) 9 PFS Kaplan-Meier 3 24.1 (OS) OS Kaplan-Meier 4 9 2 a, b 2 GAZYVA+Bendamustine GAZYVA n = 155 Bendamustine n = 166 (PFS) 13.8 ( 0.48 [0.34; 0.68] p <0.0001 ) 78.7 74.7 (CR) 15.5 18.7 (PR) 63.2 56.0 ( ) 11.6 a FL b c 12 CR PR 3 FL Kaplan-Meier 18
B: bendamustine CI G-B: obinutuzumab + bendamustine HR NR PFS 4 FL Kaplan-Meier B: bendamustine CI G-B: obinutuzumab + bendamustine HR NR OS 14. / 14.1 / GAZYVA 1000 mg/40 ml (25 mg/ml) 2 C 8 C GAZYVA 0.9 0.4 mg/ml 20 mg/ml 2 C 8 C 24 ( 30 C) 48 ( ) GAZYVA 2-8 C 24 GAZYVA 0.9 0.4 mg/ml 20.0 mg/ml GAZYVA 15. 100 CDS5.0_05.16_GAZ-3B01 2016 2 USPI 000973 Roche Diagnostics GmbH Sandhofer Strasse 116, D-68305 Mannheim, Germany 19
F. Hoffmann-La Roche Ltd Wurmisweg, CH-4303 Kaiseraugst, Switzerland 134 9 GAZYVA 20