American Society of Hematology Annual Meeting • 7-10 December 2013 • Abstract # 2860

Phase 2 Study of Otlertuzumab (TRU-016), an Anti-CD37 ADAPTIR™ Protein, in Combination with Bendamustine vs Bendamustine Alone in Patients with Relapsed Chronic Lymphocytic Leukemia (CLL)

Tadeusz Robak1, Andrzej Hellman2, Janusz Kloczko3, Javier Loscertales4, Ewa Lech-Maranda5, John M. Pagel6, Anthony Mato7, John C. Byrd8, Farrukh T. Awan9, Holger Hebart10, Jose A. Garcia-Marco11, Brian T. Hill12, Michael Hallek13, Scott Stromatt14 and Ulrich Jaeger15

1Department of Hematology, Medical University of Lodz, Lodz, Poland; 2Medical University of Gdansk, Gdansk, Poland; 3Department of Haematology, Medical University of Bialystok, Bialystok, Poland; 4Hematology, Hospital La Princesa, Madrid, Spain; 5Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland; 6Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA; 7John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ; 8Division of Hematology, The Ohio State University,

Columbus, OH; 9Georgia Regents University, Augusta, GA; 10Department of Hematology/Oncology, Stauferklinikum Mutlangen, Mutlangen, Germany; 11Hospital U. Puerta de Hierro-Majadahonda, Madrid, Spain; 12Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH; 13Department of Internal Medicine, Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne, Cologne, Germany; 14Emergent Product Development Seattle, Seattle, WA; 15GCLLSG and Medical University of Vienna, Vienna, Austria

Introduction ▪ CD37 is a tetraspanin protein expressed on the surface of normal and transformed B cells across a wide

range of maturational stages and demonstrates death signaling via SHP1. 1

▪ Otlertuzumab (formerly known as TRU-016) is a CD37-specific therapeutic protein built on the ADAPTIR™ (modular protein technology) platform.

▪ Otlertuzumab has shown significantly greater direct killing of CLL cells than rituximab and higher levels of Fc-mediated cellular cytotoxicity of CLL cells than either alemtuzumab or rituximab in preclinical models. 2

▪ Preclinical in vitro and in vivo models showed significant activity of otlertuzumab with bendamustine. 3

▪ In the phase 1b portion of this study – No dose limiting toxicities occurred at 15 or 20 mg/kg – High response rate

▪ This trial of otlertuzumab with bendamustine was conducted in patients with relapsed CLL to investigate the activity of this combination compared to bendamustine alone.

Otlertuzumab Targets CD37 on B Cells

Adapted from Lapalombella, R., Cancer Cell 21, 694-708, May 15, 2012

ADAPTIR Modular Protein Technology Targeting CD37 ▪ Humanized single chain Fv-Fc anti-CD37 protein ▪ Human IgG1 Fc supports effector function ▪ Smaller size compared to antibody ▪ MOA: ADCC, direct apoptosis and CDC

Phase 1b Response ▪ Different levels of assessment

– Best response at any time per investigator – NCI: 2 month's duration, physical exam and CBC – IWCLL: same as NCI but includes CT scan; CR 2 months-duration is after completing treatment

Event Investigator Response(N=12)

NCI Response(N=12)

IWCLL Response(N=12)

ORR 100% 83% 87.5%

CR 33% 33% 0

▪ 4 CRs under NCI did not reach IWCLL criteria – 2 patients did not have a confirmatory CT scan

– 2 patients had nodes >1.5 cm at end of study; one was 1.6 cm and the other was 1.8 cm

Bendamustine in Relapsed CLL Variability of Bendamustine Results Led to Randomized Trial 16201

Study Rx ORR CR PFS n Comments

Frontline Approval B 59% 8% 18 m ~150 100 mg/m2 days 1,2/cycle, x 6 cycles

Fischer4 BR 88% 23% 34 m 117 90 mg/m2 days 1,2/cycle, x 6 cycles; combined with RTX

Relapsed Fischer5 BR 59% 9% 15 m 78 Median 2 priors, combined with RTX 70 mg/m2 days 1,2 q28 days

Bergman6 B 56% 12% NR 16 Median 3 priors, DOR 43 m 70 mg/m2 days 1,2 q3-4 wks

Kath7 B 75% 30% NR 23 13 Rx naïve 50 or 60 mg/m2, days 1-5, q29d

Lissitchkov8 B 40% 27% NR 15 Pretreated but Fludara naïve 100 mg/m2 days 1,2 q3 wks

Aivado9 B 67% 29% 6 m TTF 21 Median 2 priors, results hematologic, OS 14 m;

100 mg/m2,days 1,2 q 4wks

Bremer10 B 93% 7% NR 15 Median 5 priors; OS ~32 m 60 mg/m2, days 1-5, q29 days

Niederle11 B 76% 27% 20 m 49 100 mg/m2 1,2/cycle x 6 cycles; 2nd line with no prior fluda or benda

Phase 2 Randomized Dosing and Assessment Schema Controlled Trial

Study Design ▪ Randomized controlled trial ▪ Relapsed CLL with 1-3 prior regimens ▪ Otlertuzumab and bendamustine vs. bendamustine alone

– Bendamustine dose 70 mg/m2

– Otlertuzumab 20 mg/kg ▪ Compare efficacy and safety ▪ Stratified

– del[17p13.1] or TP53 mutation – CIRS >6 or ≤6 – CrCl <60 or ≥60

Entry Criteria ▪ Relapsed CLL with 1 to 3 prior treatments ▪ Demonstrated active disease requiring treatment ▪ Not refractory to fludarabine or other purines, either as a single agent or in combination ▪ Age ≥18 years ▪ Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 ▪ Serum creatinine, total bilirubin, serum glutamic oxaloacetic transaminase (SGOT),

serum glutamate pyruvate transaminase (SGPT) of ≤2.0 x upper limit of normal (ULN) ▪ ANC ≥1,200/mm3 (≥1,200/μL) ▪ Platelets ≥75,000/mm3 (≥75,000/μL) ▪ Lymphocytes ≥5,000/mm3 (≥5,000/μL) in Phase 1b ▪ No rituximab (RTX) in prior 30 days or alemtuzumab within prior 12 weeks ▪ No previous anticancer therapy in prior 30 days ▪ No investigational drug in prior 30 days ▪ Must have negative serology for HIV, HCV, or HBV

Efficacy Endpoints ▪ Primary

– Overall Response Rate (ORR) by 2008 International Workshop on CLL (IWCLL) Response Criteria

▪ Secondary – ORR by 1996 National Cancer Institute (NCI) Working Group Response Criteria – Complete Response (CR) by both IWCLL and NCI criteria – Progression Free Survival (PFS) – Overall Survival (OS) – Duration of Overall Response (DOR) – Resolution of disease related symptoms

Patient Characteristics

Baseline Characteristics

Patient Characteristic Otlertuzumab + bendamustine (N=32) Bendamustine (N=33)

Age, median (range) 65 (44-82) 60 (48-79)

CIRS ≤6 81% 82%

FIT 75% 67%

CrCl <60 mL/min 19% 15%

Bulky disease (≥7 cm) 25% 18%

≥2 prior regimens 63% 39%

del(17p13.1) 13% 18%

TP53 mutation 16% 27%

Rai III/IV 28% 36%

Prior Therapies

Characteristic Otlertuzumab + bendamustine (N=32) Bendamustine (N=33)

Prior therapies, n (%)

1

2

≥3

12 (38)

14 (44)

6 (19)

20 (61)

9 (27)

4 (12)

Type of prior therapy, n

Cyclophosphamide 28 26

Fludarabine 24 23

Rituximab 27 21

FCR 16 10

Prednisone 5 6

Bendamustine 3 2

Chlorambucil 8 1

Cladribine 6 3

Lumiliximab 5 2

Vincristine 3 3

Leukeran 3 3

FCR-L 4 2

CCR 4 1

FCR = fludarabine, cyclophosphamide, rituximab; FCR-L = fludarabine, cyclophosphamide, rituximab, lumiliximab CCR = cladribine, cyclophosphamide, rituximab

Treatment Summary

Characteristic Otlertuzumab + bendamustine (N=32) Bendamustine (N=33)

Median number of cycles (range) 6 (1-6) 6 (2-6)

Total treatment duration days (range) 155 (1-192) 142 (42-169)

Patients discontinuing treatment, n (%) 7 (22) 12 (36)

Primary reason for treatment discontinuation, n (%)

Adverse event 3 (9) 8 (24)

Disease progression 3 (9) 3 (9)

Other therapy 1 (3) 0

Death 0 1 (3)

Efficacy

IWCLL Response Rate

NCI Response Rate*

*Based on 2-month duration of response

Overall Survival

IWCLL Response Rate by Risk Factor Absolute Lymphocyte Count

Safety

Adverse Events Summary

Otlertuzumab + bendamustine (N=32) Bendamustine (N=33)

Any adverse event 91% 100%

Any severe (grade 3 or 4) event 63% 73%

SAE 31% 45%

AE resulting in discontinuation 9% 24%

Death 0% 6%

Adverse Events (≥4 Patients in Either Arm)

Otlertuzumab + bendamustine (N=32) Bendamustine (N=33)

Any event 91% 100%

Neutropenia 59% 39%

Any infection 63% 64%

Pneumonia 9% 15%

Bronchitis 16% 21%

Upper respiratory tract infection 16% 9%

Thrombocytopenia 38% 27%

Anemia 31% 33%

Pyrexia 31% 12%

Nausea 19% 30%

Diarrhea 16% 21%

Fatigue 16% 15%

Cough 13% 24%

Hyperuricaemia 13% 9%

Vomiting 9% 15%

Nasopharyngitis 13% 3%

Constipation 6% 21%

Headache 6% 15%

Abdominal pain upper 6% 12%

Dizziness 3% 12%

Severe (Grade 3 or 4) Adverse Events (≥2 Patients in Either Arm)

Otlertuzumab + bendamustine (N=32) Bendamustine (N=33)

Any grade 3/4 event 63% 73%

Neutropenia 53% 39%

Thrombocytopenia 22% 12%

Any infection 13% 27%

Pneumonia 6% 12%

Bronchitis 0% 9%

Anemia 13% 15%

Febrile neutropenia 0% 6%

Serious Adverse Events (>1 Patient in Either Arm)

Otlertuzumab + bendamustine (N=32) Bendamustine (N=33)

All Related All Related

Any serious events 31% 13% 45% 18%

Pneumonia 9% 3% 12% 3%

Pyrexia 9% 3% 9% 6%

Bronchitis 0% 0% 9% 0%

Febrile neutropenia 0% 0% 6% 3%

Neutrophil Count Platelet Count

Hemoglobin Count

Pharmacokinetics

Otlertuzumab Serum Concentration ▪ Half-life ranged from 6 to 17 days, with a mean

of 11 days. ▪ Half-life for otlertuzumab in CLL patients

appeared to be slightly longer when dosed in combination with bendamustine, compared to data from a study of otlertuzumab as a single agent.

▪ Average Cmax for patients dosed with 20 mg/kg otlertuzumab was approximately 1 mg/mL, and Cmax values are similar to values seen for CLL patients dosed at the same level in a single agent study.

▪ The treatment schedule used for CLL patients maintained concentrations of otlertuzumab, with trough levels generally above 100 ug/mL.

▪ Average clearance and volume of distribution for otlertuzumab to date in study 16201 is 2.7 mL/day/kg and 41.6 mL/kg, respectively.

Otlertuzumab Pharmacokinetics (n=19)

HL Lambda z (day)

Cmax (ug/mL)

AUC (hr*ug/mL)

Vz obs (mL/kg)

Cl obs (mL/day/kg)

Vss obs (mL/kg)

Mean 10.6 1002.0 80608 41.6 2.7 35.4

STD 2.6 305.7 30349 29.6 1.3 13.0

CV% 24.3 30.5 37.7 71.2 48.5 36.6

CV%: Coefficient of variation; STD: Standard deviation; HL lambda z: Apparent terminal elimination half-life; Cmax: Maximum observed concentration; AUC: Area under the curve from the time of dosing, to the last measurable concentration; Vz: Volume of distribution based on the terminal phase; CL: Serum clearance; Vss: Volume of distribution at steady state

Conclusion ▪ Response rate with otlertuzumab in combination with bendamustine was higher than bendamustine alone

by IWCLL or NCI response criteria. ▪ The overall incidence of adverse events, severe and serious adverse events were generally similar between

the cohorts. Of clinical importance is the greater incidence of severe neutropenia with the combination, but this did not result in a greater incidence of severe or serious infections.

▪ No increase in serious adverse events in the otlertuzumab plus bendamustine arm compared to the bendamustine arm.

▪ These results support further studies with otlertuzumab. A phase 1b trial of otlertuzumab and rituximab in treatment-naive CLL patients is ongoing (poster #4165).

References1Lapalombella R, Yeh YY, Wang L, et al. Cancer Cell 21:694-708, 20122Zhao X, Lapalombella R, Joshi T, et al. Blood 110:2569-77, 20073Algate PW, J.; Nilsson, C.; Sho, M.et al. Blood 116:3931, 20104Fischer K, Cramer P, Busch R, et al. J Clin Oncol 29:3559-66, 20115Fischer K, Cramer P, Busch R, et al. J Clin Oncol 30:3209-16, 20126Bergmann MA, Goebeler ME, Herold M, et al. Haematologica 90:1357-64, 2005

7Kath R, Blumenstengel K, Fricke HJ, et al. J Cancer Res Clin Oncol 127(1):48–54, 20018Lissitchkov T, Arnaudov G, Peytchev D, et al. J Cancer Res Clin Oncol 132:99-104, 20069Aivado M, Schulte K, Henze L, et al. Semin Oncol 29:19-22, 200210Bremer K. J Cancer Res Clin Oncol 128:603-9, 200211Niederle N, Megdenberg D, Balleisen L, et al. Ann Hematol 92:653-60, 2013

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Otlertuzumab (20 mg/kg)

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Bendamustine (70 mg/m2)

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