Nimotuzumab Paul Keane MD, FRCPC, FACP, FRC Path

Transcription

1 Nimotuzumab Paul Keane MD, FRCPC, FACP, FRC Path Research & Development Day Wednesday April 5, 2006 Harvard Club New York City

2 EGFR The EGFR is a member of the ErbB family of tyrosine kinase (TK) receptors found on the cell surface of normal and malignant tumor cells EGFR is a central molecule in the regulation of normal and malignant cell function EGFR activation is associated with control of cellular proliferation, protection from apoptosis, and the production of proinflammatory and proangiogenic cytokines EGFR activation seems to protect malignant cells from chemotherapy- and radiotherapy-induced cell death Blocking EGFR activation enhances tumor specific destruction by standard chemotherapy agents and radiotherapy

3 Nimotuzumab This antibody blocks ligand binding to EGFR by interacting with the 3A epitope of the extracellular domain of the receptor. It binds to EGFR viii Is a human IgG 1 Inhibits activation of receptor protein tyrosine kinase Inhibits growth of EGF-dependent tumor cells in vitro and tumor growth in xenograft models Capable of mediating CDC and ADCC activity Preclinical xenograft experiments show nimotuzumab (Kd = 10-9 ) to be equivalent to Erbitux (cetuximab, Kd = ) and KSB202 (sheep chimeric antibody, very high affinity Kd = ).

4 Anti-EGFR Antibodies Product Erbitux (Cetuximab) Nimotuzumab (h-r3) Matuzumab (EMD 72000) Panitumumab (ABX EGF) Company ImClone/ Merck/BMS CIMYM/ Oncoscience Biocon IGK Kunhill BPL Merck KGaA Takeda Abgenix/ Amgen Type of Molecule Chimeric mab Humanized mab Humanized mab Fully Human mab Affinity (M) Ig Subclass IgG 1 IgG 1 IgG 1 IgG 2 Clinical Status Marketed Phase II Phase II Phase III Initial Indications Head and Neck Colorectal Glioma Head and Neck NSCLC Gastric mcrc NSCLC

5 In vivo effects of anti-egfr Mabs on A431 Xenografts in SCID Mice Effect of 4 doses of various anti-egfr Mabs versus saline control (Average tumor volume for each group) Tumor volume Days of injections Days after cell inoculation Days of dosing PBS (control) C225 (cetuximab) m-r3 h-r3 (nimotuzumab)

6 Xenograft Comparison of Nimotuzumab and KSB HN-5 xenograft study Stage I Tumor Volume (mm 3 ) Control KSB ug/dose KSB ug/dose KSB ug/dose KSB ug/dose nimotuzumab 50 ug/dose nimotuzumab 100 ug/dose nimotuzumab 200 ug/dose nimotuzumab 400 ug/dose 0 Day 0 Day 4 Day 7 Day 11 Day 14 Day 18 Day 21 Day 24 Day 28 Day 35 Day 39 Day 42 Day 46

7 Decoupling Efficacy and Side Effects Nimotuzumab differs markedly from other agents employed therapeutically to block EGFR function in that the treatment related incidences of rash, diarrhea and conjunctivitis are negligible. Yet there is strong evidence of the efficacy of nimotuzumab in a variety of clinical settings. These observations, whilst on the surface being counterintuitive, are we believe explicable on the basis of the dose and affinity constant of the antibody.

8 Side Effect Profiles of EGFR Antibodies Treatment-Related Side Effects of HER1/EGFR Inhibition Anti-EGFR MAb Studies Rash Diarrhea Conjunctivitis Erbitux (Cetuximab) Pancreatic CRC (w/irinotecan) CRC (monotherapy) Head and Neck 55% 88% 90% 34% 54% 72% 25% ~14% Matuzumab monotherapy (CRC (50%), H&N (18%), other (32%)) 64% 23%? Tarceva monotherapy 75% 54% ~12% Panitumumab monotherapy 100% 6% ~17% Nimotuzumab various rare rare rare

9 Review of Nimotuzumab Clinical Data

10 Clinical Studies Using Nimotuzumab 24 patient Phase II head and neck trial in Canada (2003) 34 patient trial in children with glioma in Germany (2005) 24 patient adult glioma trial presented at ASCO (2005) 24 patient head/neck trial published in the Journal of Clinical Oncology (2004) 130 patient pivotal Phase II which led to the approval of the drug in China (2005) 96 patients in a randomized Phase II H&N ongoing (2005) 84 patients in a Phase III H&N ongoing (2005) 60 subject study in advanced pancreatic cancer (Germany)

11 Head and Neck Cancer Nimotuzumab with radiation in LAHNC median overall survival (months) Study 1 44 Study 2 43 Erbitux * (cetuximab) 49 Radiation* 29 * Historical control Nimotuzumab with radiation compared with radiation in NPC Nimotuzumab plus radiation 92% Radiation alone 53% Complete tumour response rate

12 Glioma Adult glioma Nimotuzumab plus radiation following surgery: Overall survival 18 months Surgery plus radiation *: Overall survival 12 months * Recurrent refractory intrinsic pediatric pontine glioma Multiple doses of nimotuzumab given as monotherapy: Of 14 cases, 9 showed clinical benefit (1 PR; 8 SD)

13 Pontine Glioma (continued) Oncoscience AG presented at 27th Annual German Cancer Conference Berlin, March 25th, 2006 Phase II study with 40 patients Reported 8 of 40 patients were evaluable for response after consolidation therapy : three partial responses (PR), one stable disease (SD) and four progressive disease (PD) in week 21 Eight patients with consolidation therapy were free of progression for a median of 4.6 months ( months). Eight children out of the 40 recruited into the trial were still living as of March 25 th ( months) Non-responders to treatment had a median survival of 1.1 months No severe side effects and no rash, diarrhea or conjuctivitis related to study medication were observed.

14 MRI Scans : Before and After Nimotuzumab Therapy

15 Nimotuzumab as Monotherapy Nimotuzumab as monotherapy in patients with refractory, heavily pretreated solid tumors - 11 patients enrolled, 10 with advanced CRC Nimotuzumab weekly for 7 weeks, then every 3 weeks in non-progressors Diagnosis Dose and (#) Previous Therapy* Response Metastatic CRC 100 mg. (21) S, SMAC SD Mesothelioma 200 mg. (9) S, SMAC PR Metastatic CRC 400 mg. (6) S, SMAC SD Metastatic CRC 400 mg. (7) S, SMAC SD * S = surgery, SMAC = Systemic Multi Agent Chemotherapy

16 Efficacy Conclusion The preceding slides present strong evidence for the efficacy of nimotuzumab in a variety of clinical settings. Most impressive are the results obtained with monotherapy in patients with recurrent pontine glioma and refractory solid tumors. These results have been obtained in the absence of side effects frequently encountered with EGFR blockade treatment regimens.

17 Dose Finding and Pharmacokinetics The evidence of efficacy presented here in the virtual absence of side effects commonly associated with EGFR blockade is unexpected but we believe it can be explained. The explanation relates to the doses and affinity constants of antibodies used. Dose finding in this therapeutic area is a complex process. Despite the fact that EGFR antibodies display nonlinear pharmacokinetics, classical small molecule PK approaches have been used to define antibody doses at which saturation of systemic clearance occurs.

18 Dose Finding Erbitux (Cetuximab): Classical small molecule PK approach with definition of saturation of systemic clearance. Matuzumab: Extensive PK and PD studies. Whilst this antibody was shown to be effective in head and neck cancer at 200 mg weekly, a final convenient dose of 1200 mg q 3 weeks is used. Panitumumab: Dosed to 100% rash at 2mg/kg. The IC 90 for clearance saturation being 1.5 mg/kg. Nimotuzumab: Whilst the dose for saturation of systemic clearance has been computed at 250 mg, doses of 100 to 400 mg/week have been used in combination with radiation. There is minor evidence of efficacy at 100 mg as monotherapy and good evidence of efficacy as monotherapy in children at 150 mg/m 2.

19 Affinity Constants The notion that high affinity constants are better relates to their use in immunoassay systems but is not applicable to in vivo situations, e.g. receptor or antigen mediated tumor uptake. Solid tumor uptake is determined more by receptor density than antibody affinity, within certain limits.

20 Antibody Affinity and Solid Tumor, Xenograft Uptake Antibody has an affinity constant two orders of magnitude higher than 436 yet tumor uptake is not different

21 Antibody Uptake as a Function of Receptor Density Receptor density is 3 times greater on 436 than INI1

22 EGFR antibody distribution curves between tumor, liver, skin and plasma have been modeled for a variety of antibodies at different doses

23 Antibody Distribution Post Injection When injected i.v. EGFR antibodies will distribute as shown below. The relative tissue uptake with time will be a function of receptor density, dose, plasma half life and antibody affinity constant K D, Bo Liver Plasma Skin Tumor

24 Modeling of Relative Distributions dcp (t) dc p(t) Cp(t) C = D ( dt dt Vp Ttumor (t) C V T Btumor C ) ( TLiver (t) C V L BLiver C ) ( TSkin (t) C V S BSkin ) dc Ttumor dt (t) Cp(t) C T tumor (t) CB tumor = Dtumor ( ) Vp VT (2) dc T Liver dt (t) Cp(t) C TLiver (t) CB Liver = DLiver ( ) Vp VL dc T Skin dt (t) C p(t) CTSkin (t) CB Skin = DSkin ( ) Vp VS Figure 1: The 4 differential equations describe the changes in antibody concentration in plasma, tumor, liver and skin respectively as a function of time (t), tissue volume (V) and a speed of clearance parameter (D) which was estimated from previous pharmacokinetic data.

25 Modeling Results Dependence of the of AUC the vs AUC K D for vsthe K D for doses dosis of of mg mg Dependence of the of AUC the vs AUC K D for vsthe K D for doses dosis of of mg mg AUC (nm/l x hr) Skin Liver AUC (nm/l x hr) Skin Liver Tumor Tumor K D (M) K D (M)

26 Modeling Results The following slides show the modeled distributions of 200 mg doses of nimotuzumab, cetuximab and panitumumab using available data for affinity constants, PK half lives and assuming that tumor receptor density is 10 6 /cell and 10 4 /cell in normal tissues.

27 Modeling Results Nimotuzumab (h-r3) ERBITUX (C225) AUC (nm/l x h) K D = (4.53 ± 1.05) x M Skin Liver Tumor AUC (nm/l x h) K D = 5.0 x M Skin Liver Tumor K D (M) K D (M) Panitumumab (ABX-EGF) AUC (nm/l x h) KD =5.0 x M 5000 Skin Liver Tumor K D (M)

28 A more transparent approach may be to consider the presence or absence of rash as a combined linear function of both dose and affinity constant.

29 Kd Dose Product Antibody Normalized Kd to nimotuzumab Dose mg/week Kd. Dose Rash % Nimotuzumab Matuzumab Cetuximab Panitumumab ,

30 Efficacy and Safety Conclusions We have presented firm evidence of the efficacy of Nimotuzumab in the absence of rash. The logical explanation is that the appearance of rash is a function of both dose and affinity constant. High values of either will favor enhanced uptake of antibody by EGF receptors in skin. Perhaps a more important question is: Why do some patients not get rash?

31 Nimotuzumab Development Plan

32 Nimotuzumab Clinical Development Program Head & Neck (completed - Canada) Completed Studies, Ongoing Studies Pre-Clinical Phase I Phase II Phase III Market Head & Neck (completed) (Latin America) America) Nasopharyngeal (completed ) (China) Paediatric Brain (monotherapy completed) Marketed Argentina/Columbia Marketed - China Pontine Glioma Gloma (+ radiation) Metastatic Pancreatic Pharmacodynamic Study Head & Neck (India) NSCLC (Canada & Korea) I / II

33 Nimotuzumab Clinical Development Program (cont d) Completed, Ongoing, Planned SCCHN Head + Radiation & Neck (+ Radiation) Malignant Brain (+ + Radiation) Pre-Clinical Phase I Phase II Phase III Market HRPC (+ Chemotherapy) Esophageal (+ chemoradiotherapy) SCCHN (+ Radiation) Breast (+ Chemotherapy) Uterine Cervix (+ Radiation + Brachytherapy)

34 Nimotuzumab Future Opportunities Adult Glioma Target patients with unmethylated MGMT promoter gene (50% of all glioma patients) Diffuse Pontine Glioma First line or second line therapy Colorectal Cancer Adjuvant/neoadjuvant using nimotuzumab plus chemoradiation Refractory colorectal cancer a. nimotuzumab plus chemotherapy b. nimotuzumab monotherapy

35 Nimotuzumab Paul Keane MD, FRCPC, FACP, FRC Path Research & Development Day Wednesday April 5, 2006 Harvard Club New York City