Toca 511= virus + CD gene

SNI Clinical Trials Neuro-oncology

SNI Clinical Trials Neuro-oncology Glioblastoma – Newly diagnosed • Immunotherapy - DCVax- tumor antigen pulsed dendritic cells - Celldex- EGFR VIII mutant vaccine

• Small molecule VEGF inhibitor - cediranib

• NovoCure TTF device

High grade glioma – Recurrence • Retroviral gene therapy

-cytosine deaminase prodrug conversion

SNI Clinical Trials Neuro-oncology GBM Newly Diagnosed - Phase II

ACT IV A Randomized, Double-Blind, Controlled Study of Rindopepimut/GM-CSF with Adjuvant Temozolomide in Patients with Newly Diagnosed, Surgically Resected, EGFRvIII-positive Glioblastoma

The EGFR Mutation Variant III (EGFRvIII) EGF-binding domain

Transmembrane domain

Intracellular domain

NH2

COOH

wtEGFR EGFRvIII

• Tumor-specific oncogene ideally suited for immune targeting • Expressed in 1/3 of primary glioblastoma, but not in normal tissue

• In-frame deletion of exons 2-7 results in constitutively active protein with unique amino acid sequence at the fusion junction • Epitope is in the extracellular domain; accessible to antibodies and highly immunogenic

Rindopepimut (CDX-110) Vaccine designed to generate a specific immune response against EGFRvIII-expressing tumors • “Off the shelf” vaccine recognized across HLA types • Consists of the EGFRvIII antigen (unique 13 amino acid peptide

sequence) chemically conjugated to Keyhole Limpet Hemocyanin • Delivered as intradermal injection of 500ug rindopepimut with 150ug GM-CSF • Stable lyophilized formulation

O N O S

N

KLH

O

LEEKKGNYVVTDHC >30

ACT IV Study Design R A N D O M I Z A T I O N

Vaccine Priming

Adjuvant Temozolomide and Vaccine Therapy (TMZ-V, 6-12 cycles)

Vaccine Maintenance Therapy (VMT)

§

§

D1

D15

• Dose vaccine days 1 and 15 of Vaccine Priming cycle • Start cycle within 4 days after randomization and within 7-14 days after completion of CRT

C1D1

C1D22

C2D22

C3D22

etc….

• Vaccine or placebo is administered Day 22 of each TMZ cycle • Begin TMZ no sooner than 6 days after administration of the second vaccine priming dose • Begin TMZ no sooner than 28 days after completion of CRT

• Begin TMZ when ANC  1000/L and platelets  100,000/L

Follow Up

C1D1

C2D1 etc…

If no disease progression after TMZ, continue dosing vaccine every 28 days (Day 1 ±3 days of each 28 day cycle) until intolerance or disease progression

Follow-up for overall survival every 12 weeks after disease progression

• TMZ dosed days 1-5 of each 28 day cycle

§

CRT

Temozolomide Dosing Vaccine or Placebo Dosing Tumor Assessments – every twelve weeks Chemoradiation Therapy

Treatment will be discontinued upon disease progression, unacceptable treatment-related toxicity, or patient refusal to continue study treatment

SNI Clinical Trials Neuro-oncology GBM Newly Diagnosed - Phase II

DCVax-L An Autologous, Dendritic Cell Based Therapeutic Vaccine for Newly Diagnosed Glioblastoma Multiforme

SNI Clinical Trials Neuro-oncology DCVax-L Vaccine produced from: - Autologous dendritic cells generated from PBMC - Pulsed with autologous GBM lysate - Subcutaneous vaccine injections - During adjuvant TMZ

SNI Clinical Trials Neuro-oncology GBM Recurrence - Phase I

Tocagen 511 A Phase 1 Ascending Dose Trial of the Safety and Tolerability of Toca 511, a Retroviral Replicating Vector, Administered to Subjects at the Time of Resection for Recurrent High Grade Glioma and Followed by Treatment with Toca FC, Extended-Release 5-FC

Toca 511 delivers yeast cytosine deaminase gene into replicating tumor cells U3

R U5

gag

pol

env

U3

R U5

 IRES

5-FC • 5-FC is orally available • 5-FC crosses the BBB

CD

Cytosine Deaminase

5-FU

Infected tumor cells convert 5-FC to 5-FU Toca 511 injected into tumor

5-FC taken orally

Toca 511

5-FC

5-FU CD

Tumor

Normal tissue

Toca 511 spreads through tumor Toca 511= virus + CD gene

2012 Copyright Tocagen Inc.

Tumor regression

SNI Clinical Trials 30

Translational Studies MS

Clinical Studies

25

Brain Tumor

N = 79

20

15

Pituitary

Epilepsy

10

Spine

Cerebrovascular

5

Neuro-ophth

Movement Disorders

Psychiatry Stroke

0

Research Patient Enrollment 800 700 600 500 400 300 Dec-10 Jan-11 Feb-11 Mar-11 Apr-11 May-11 Jun-11

Jul-11

Aug-11 Sep-11 Oct-11 Nov-11 Dec-11 Jan-12

SNI Clinical Trials

Swedish Neuroscience Inst