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Entwicklung und Zulassung des trifunktionalen Antikörpers Removab (catumaxomab)

Dr. Diane Seimetz BioM -

Forum, 14. November 2008 © Fresenius SE

Agenda Trifunctional Antibodies – Technology and Mechanism of Action Nonclinical Development Clinical Development Approval Process

© Fresenius SE

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Trifunctional Antibodies Comprise a New Quality of Antibody-Mediated Tumor Cell Killing Conventional antibody

Bispecific antibody

Trifunctional antibody

Tumor cell

Tumor cell

Tumor cell

Molecular design

Access. cell

Modes of action

Examples

T-cell

T-cell

Access. cell

1 Ab-mediated cell killing (ADCC1))

Rituxan, Herceptin

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T-cell mediated cell killing

In clinical development

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Ab-mediated cell killing (ADCC1))

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+ T-cell mediated cell killing

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+ Anti-tumor immunity Submitted for approval In clinical development

1) Antibody-dependent cell-mediated cytotoxicity © Fresenius SE

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The Trifunctional Hybrid-Hybridoma Construct (Mouse IgG2a/ Rat IgG2b) Offers Major Advantages

α-TAA(1)

α-CD3

Advantages of mouse/rat hybrid

On production „ Species restricted heavy/light chain pairing „ Easy hybrid Fc-pairing due to homologous sequence

On effector functions „ Binding to activating Fcγ RI, Rlla and Fcγ RIII on accessory cells mouse IgG2a

rat IgG2b

„ No or minimal binding to inhibitory Fcγ RIIb

1) Tumor associated antigen Lindhofer H et al. J Immunol 1995; 155: 219-25.; Zeidler R et al. Br J Cancer 2000; 83: 261-266 © Fresenius SE

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Trifunctional Antibodies Smartly Involve Immune Cells In Tumor Cell Killing

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Tumor Cell

EpCAM

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Lysis Apoptosis

T-Cell

Signal 1 2 CD3

Activation CD40L / CD28 / CD2

ADCC Phagocytosis Apoptosis CDC

CD40 / B7.1-2 / LFA-3 Fcγ RI/IIa/III 1

IL-1, IL-2 IL-12, IL-6 TNF-α, INF-γ DC-CK1 GM-CSF

Physiological co-stimulation

Fcγ-RI, Rlla or RIII+ Accessory Cells macrophages, dendritic cells, natural killer cells 3 Immunization

Source: Ruf & Lindhofer, Blood 98, 2526-34, 2001 © Fresenius SE

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© Fresenius SE

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Agenda Trifunctional Antibodies – Technology and Mechanism of Action Nonclinical Development Clinical Development Approval Process

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Essential Considerations for the Nonclinical Program

Tumor Cell

T-Cell

ƒ

Specificity of Removab for human target antigens

ÆStandard preclinical in vivo models are of limited value

ƒ

Design a targeted nonclinical testing program

ÆUse of surrogate model

Accessory Cell

systems (e.g. BiLu; anti-human EpCAM x anti-mouse CD3 antibody)

© Fresenius SE

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Nonclinical Development Program: Pharmacology ƒ

Pharmacodynamic studies in vitro (selection)

ƒ ƒ ƒ ƒ

ƒ

Binding to target antigens on tumor cells, T-cells and accessory cells Activation of T-cells and induction of cytokine release Tumor-cell killing at low ng/ml concentrations; killing of apoptosis resistant tumor cells No induction of histamine release; no increased proliferation of tumor cells

Pharmacodynamic studies in vivo

ƒ ƒ

Delay of tumor development in a xenograft mouse model of ovarian carcinoma

ƒ

Binding to CD3 on lymphocytes results in a transient decrease in lymphocyte counts in a mouse model using BiLu

Inhibition of tumor growth and induction of antitumor immunity using BiLu in a syngeneic mouse tumor model expressing human EpCAM

© Fresenius SE

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Nonclinical Development Program: Pharmacokinetics ƒ

Pharmacokinetic studies

ƒ Specific tumor cell targeting of catumaxomab in a xenograft mouse tumor model

ƒ Shorter half-life of BiLu (binding to mouse CD3) compared to catumaxomab in mice

ƒ Bioavailability of BiLu after i.p. administration in healthy mice ƒ i.p. injected human target cells influence systemic exposure of catumaxomab after i.p. administration in SCID mice

© Fresenius SE

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Nonclinical Development Program: Toxicology ƒ

Toxicology studies

ƒ

No substance-related acute toxicity after single i.v. administration of catumaxomab in mice and rats

ƒ

No symptoms of disease after i.p. administration of catumaxomab in mice and guinea pigs

ƒ

No effects on clinical signs, body weight, hematologic and biochemical parameters after i.v. infusion of escalating doses of catumaxomab in a cynomolgus monkey

ƒ

Escalating doses of BiLu were tolerable for mice

ƒ

No signs of local intolerance after administration of catumaxomab in rabbits or a cynomolgus monkey and after administration of BiLu in mice

© Fresenius SE

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Agenda Trifunctional Antibodies – Technology and Mechanism of Action Nonclinical Development Clinical Development Approval Process

© Fresenius SE

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Malignant Ascites - Clinical Symptoms

Malignant Ascites „ is an increased accumulation of protein-containing fluid within the peritoneal cavity caused by intraperitoneal spread of cancer „ is mainly associated with ovarian cancer, gastrointestinal malignancies and carcinomas of other origin at late stage of the disease „ leads to ƒ abdominal pain and swelling ƒ nausea and vomiting ƒ malnutrition and anorexia ƒ dyspnea Æ thereby leading to a poor quality of life

© Fresenius SE

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Malignant Ascites - Pathophysiology Intraperitoneal spread of tumor cells is the main cause of malignant ascites

© Fresenius SE

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Rationale for Using Removab as Targeted Intraperitoneal Therapy of Malignant Ascites ƒ

Epithelial tumors spreading into the peritoneal cavity play a major role in malignant ascites formation.

ƒ

Epithelial tumors frequently express the epithelial cell adhesion molecule (EpCAM).

ƒ

In the peritoneal cavity EpCAM is a tumor-specific antigen.

ƒ

Immune effector cells are present in malignant ascites.

„ Targeting of EpCAM by intraperitoneal administration of Removab leads to ƒ a depletion of epithelial tumor cells in the peritoneal cavity ƒ a sustained reduction of malignant ascites production

© Fresenius SE

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Clinical Development Malignant Ascites (EU) - Overview Dose Finding Study (STP-REM-01)

Indication: Malignant Ascites due to OvCa

PK/PD Study (IP-REM-PK-01-EU)

Indication: Malignant Ascites due to OvCa and Non-OvCa

Results:

Pivotal Study (IP-REM-AC-01) Indication: Malignant Ascites due to OvCa and Non-OvCa

Results: Statistically significant and clinically relevant superiority of catumaxomab over control

Recommended dose 10-20-50-150 µg Efficacy: Reduction of ascites flow No requirement of puncture in 22/23 pat. at study end

© Fresenius SE

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Pivotal Study IP-REM-AC-01 - Study Design ƒ ƒ ƒ

Two-arm, randomized, open-label study Two strata, independent sample size calculation (ovarian cancer, non-ovarian cancer) 4 i.p.-infusions at 10, 20, 50 and 150 µg of Removab on day 0, 3, 7 and 10

129 patients with malignant ascites due to ovarian cancer

129 patients with malignant ascites due to non-ovarian cancer

Randomization ratio (2:1) (Removab : control)

Paracentesis plus Removab

Paracentesis alone Optional Single Arm Cross-over

Paracentesis plus Removab

© Fresenius SE

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IP-REM-AC-01 - Objectives

„

Puncture free survival defined at ƒ Time to first therapeutic puncture or ƒ Time to death, which ever occurs first

„

Time to first need for therapeutic ascites puncture

„

Time to death without therapeutic ascites puncture

„

Overall Survival

„

Safety and tolerability

„

Pharmacodynamics, e.g. tumor cell reduction in ascites fluid

„

Ascites Signs and Symptoms

Primary

Main Secondary

© Fresenius SE

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© Fresenius SE

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IP-REM-AC-01 – Main Inclusion Criteria

ƒ Resistant to chemotherapy or chemotherapy no longer feasible ƒ At least 1 previous puncture within 5 weeks before screening ƒ Symptomatic ascites with a volume of > 1 l ƒ EpCAM+ tumor cells in ascites ƒ Karnofsky Index ≥ 60

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Efficacy Results – Puncture Free Survival Pooled Analysis of Ovarian and Non-Ovarian Cancer Patients

Estimated Puncture-free Survival Probability (%)

100 90 80

Treatment:

70

catumaxomab (n=170) Control (n=88)

60 50 40 30 20 10 0 0

20

40

60

80

100

120

140

160

180

200

Time (days) to event

Median puncture free survival in days Pooled Population

Ovarian Cancer Stratum

Non-Ovarian Cancer Stratum

Gastric Cancer Subpopulation

Catumaxomab (Number of pat. with event)

46 (119)

52 (56)

37 (63)

44 (39)

Control (Number of pat. with event)

11 (82)

11 (42)

14 (40)

15 (18)

Difference [Factor]

35 [4.2]

41 [4.7]

23 [2.6]

29 [2.9]

<0.0001

<0.0001

<0.0001

<0.0001

P-value (log-rank test)

© Fresenius SE

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Efficacy Results – Time to First Puncture Pooled Analysis of Ovarian and Non-Ovarian Cancer Patients

Estimated Probability of Being Puncture-free (%)

100 90 80

Treatment:

catumaxomab (n=170)

70

Control (n=88)

60 50 40 30 20 10 0 0

20

40

60

80

100

120

140

160

180

200

Time (days) to event

Median time to first need for therapeutic ascites puncture in days Pooled Population

Ovarian Cancer Stratum

Non-Ovarian Cancer Stratum

Gastric Cancer Subpopulation

Catumaxomab (Number of pat. with event)

77 (64)

71 (36)

80 (28)

118 (15)

Control (Number of pat. with event)

13 (69)

11 (42)

15 (31)

15 (14)

Difference [Factor]

64 [5.9]

60 [6.4]

65 [5.3]

103 [7.9]

<0.0001

<0.0001

<0.0001

<0.0001

P-value (log-rank test)

© Fresenius SE

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Efficacy Results – Overall Survival Estimated Overall Survival Probability (%)

100

Pooled Analysis of Ovarian and Non-Ovarian Cancer Patients

90 80 Treatment:

70

catumaxomab (n=170)

60 Control (n=88)

50 40 30 20 10 0 0

60

120

180

240

300

360

420

480

540

Time (days) to event

Median overall survival in days Pooled Population

Pooled Population (per protocol)

Ovarian Cancer Stratum

Non-Ovarian Cancer Stratum

Gastric Cancer Subgroup

Catumaxomab (Number of pat. with event)

72 (144)

86 (107)

110 (66)

52 (78)

71 (43)

Control (Number of pat. with event)

68 (38)

68 (34)

81 (14)

49 (24)

44 (12)

4

18

29

3

27

0.0846

0.0085

0.1543

0.4226

0.0313

Difference p-value (log-rank test)

© Fresenius SE

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IP-REM-AC-01 - Summary of Safety Results

ƒ Most of the patients received all 4 infusions: 86 % ovarian cancer patients; 80.5 % non-ovarian cancer patients

ƒ Most frequent AEs were related to cytokine release and expected due to catumaxomab’s mode of action

ƒ Transient increases in liver enzymes and bilirubin as well as transient decreases of lymphocytes were rarely considered clinically significant

ƒ In the randomized part of the study, none of the deaths were considered to be related to catumaxomab treatment

ƒ In the cross-over period, one patient died due to a hypovolemic shock, possibly related to catumaxomab

ƒ The safety results of both strata showed a very similar pattern

© Fresenius SE

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Conclusions ƒ Four intraperitoneal infusions of catumaxomab result in a statistically significant benefit over control for puncture free survival and puncture free time.

ƒ Patients with symptomatic malignant ascites benefit regardless of the origin of the primary tumor.

ƒ The trend towards improved overall survival supports the positive effect of catumaxomab.

ƒ The safety profile is essentially that based on catumaxomab’s mode of action and supports the positive benefit-risk balance.

© Fresenius SE

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© Fresenius SE

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Agenda Trifunctional Antibodies – Technology and Mechanism of Action Nonclinical Development Clinical Development Approval Process

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Overview Pre- and Postsubmission Phase

Validation Phase EMEA

Submission

Administrative Process

Evaluation Process

Document Generation and Dossier Compilation Process

Š Fresenius SE

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Overview Presubmission Phase

Administrative Process

Document Generation Process at Functional Departments

Dossier Compilation Process at RA Department Submission 21 Dec07 Mar07

Apr07

May07

Jun07

Jul07

Aug07

Sep07

Oct07

Nov07

Dec07

Jan08

Š Fresenius SE

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Dossier Preparation: Responsibilities Dossier Compilation RA Department

M1 RA Department

Module 2

Clinical Composite Clinical/Safety Department

Quality Composite TRION

Nonclinical Composite Nonclinical Department Š Fresenius SE

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Overview - EU Approval Process

Submission

Assessment I

80

Clock Stop

120

Assessment II

121

150

Clock Stop

180

Oral Expl.

CHMP Opinion

181

EC Decision

210

Dec 07 Early 2009 GCP Inspection

Š Fresenius SE

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Key Factors to Consider

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Early and continuous involvement of regulatory agencies in the drug development process – biotech and targeted product – new indication

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Awareness of the complexity of a centralized procedure; “all company task”

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Implement as early as possible appropriate infrastructure and dedicated teams for each discipline

© Fresenius SE

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© Fresenius SE

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Acknowledgement

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Microsoft PowerPoint - 3_Seimetz_Fresenius.ppt