Allovectin--7®

Allovectin
Systemic Immunotherapy for Melanoma

Alain P. Rolland, Pharm.D., Ph.D.

E
Executive
ti Vi
Vice PPresident,
id t P Product
d tD Development
l t

November 9, 2010
Allovectin-7
Allovectin 7® Immunotherapy
 Systemic immunotherapy
 Bicistronic plasmid: HLA-B7 and β2 microglobulin
 Formulated with DMRIE:DOPE
 Single-vial formulation
 Intralesional injection
 Initial application in metastatic melanoma
 Excellent safety profile in multiple clinical trials
 Clinical benefit demonstrated in Phase 2
 Enrollment
E ll t off pivotal
i t l Ph
Phase 3 under
d SPA completed l t d
 Potential additional solid tumor applications
 Head & neck;; breast;; lung;
g; prostate
p
 Allovectin-7
Allovectin 7® Administration
 Direct intratumoral injection
 Repeat injections into single tumor lesion
 Cycle
C l = 1/1/wk
k x 6 wks
k + 2 wksk observation
b ti
 Outpatient setting
 No pre-treatment or post-treatment care
 Well-tolerated in multiple clinical trials
 Minimal impact on QOL

3
Mechanisms of Action
 Allogeneic anti-tumor
anti tumor Plasmids transfect tumor cells
response
 HLA-B7

 Up-regulation / restoration
of MHC Class I – tumor HLA-B7 and -2 microglobulin
expressed: MHC Class I
antigen presentation presentation to immune system

 2-microglobulin

 Pro
Pro-inflammatory
inflammatory effect of Immune tumor destruction
(e.g., T cells, macrophages);
lipid / DNA complex tumor antigen recognition
and spreading
 Lipids, CpG motifs, TLR9
SYSTEMIC
EFFECT
LOCAL
EFFECT
 Allovectin-7® & Anti CTLA-4 mAb
Complementary Mechanisms of Action
T Cell Potentiation
T Cell

Activated MHC Ag TCR

Antigen
T Cell Presenting
CD28 T Cell
Cell CD80/86
CTLA-4
Tumor MHC
Class I
Cell

Tumor-associated Anti CTLA-4 mAb

antigens (TAAs)
Antigen T Cell Inactivation
Presenting
Cell
Allovectin-7®
MHC Ag TCR
Antigen
1. Increased recognition and destruction Presenting CD28 T Cell
of tumor cells expressing HLA B7/2M Cell
CTLA-4
by T cells CD80/86
2. Increased presentation by APCs to T cells
of TAAs released from tumor cells
Allovectin-7
Allovectin 7® Large Phase 2 Trial
 Phase 2
2, open-label
open-label, multi-center
multi-center, dose-escalation trial
 Stage III or IV metastatic melanoma
 N =133 (0.5 mg (N=3); 1 mg (N=3); 2 mg (N=127)
 Efficacy stage (2 mg)
 127 patients with Stage III (53%) or Stage IV disease (47%)
 Single injectable lesion or
 Multiple injectable lesions, randomized to single or multiple
injected lesions (up to 5 lesions)
 Response rate (RECIST)
 Duration of response
 Survival
 Safety
 Allovectin-7® Phase 2 Data
In Metastatic Melanoma Patients
DTIC* Ipilimumab**
p Allovectin-7®
(Genta P3 Trial) (BMS P3) (Phase 2)

N= 385 137 127

Treatment Withdrawal 10.8% NA 0%
Grade 3 and 4 Events 22% 23% 0%
Response Rate 7.5%
7 5% 10.9%
10 9% 11.8%
11 8%
Durable Response 3.6% NA 11.8%
(> 6 months)
P3 target population 4% NA 17%
Duration of Response 4.1 mo NR 13.8 mo
(6 mo - 66+ mo)
Median Survival 7 8 mo
7.8 10 1 mo
10.1 18 8 mo
18.8
* Historical control from Genasense Phase 3 trial
** Hodi et al. 10.1056/NEJMoa1003466
Survival
Allovectin-7® Responders vs Overall Patients
Time to Death from Date of First Injection
Kaplan-Meier Estimate (2mg dose)

Median survival

Median Survival = 18
18.8
8 Months
95% CI (14.8 - 26.2)

Plotted circles represent censored data

 Overall Survival Comparison
Allovectin-7®
1
1-year survival:
i l 65%
2-year survival: 43% • Allovectin-7®

Overall mean 1-year survival rate

95% confidence bounds

 Meta-analysis of 42 Cooperative Group Phase 2 trials (70 trial arms)

with 2,100 metastatic melanoma patients (Korn et al., J. Clin. Onc. 2008)
 Median survival: 6.2 months (95% CI, 5.9-6.5 months)
 Overall mean 1-year survival rate: 25%
 No trial arm statistically different from mean 1-year rate based on 95% confidence bounds
 Allovectin-7® Phase 2 survival results fall outside the confidence interval
(i.e., significantly better than the mean)
Allovectin-7® Phase 2 Key
y Points
Incorporated into Phase 3 Trial Design
 Entry criteria
 No brain mets or visceral mets other than lung (Stage III/IV ≤ M1b)
 Normal LDH
 Chemonaïve ((11/15 responders
p in Phase 2))
 Treatment
 Single lesion injected with 2 mg dose (14/15 responders in Phase 2)
 Modified RECIST criteria
 Patients assessed only qualitatively for palliative therapy after 1 cycle
 Definitions for clinically non-significant lesions prior to Week 16
 First formal efficacyy evaluation at 2 cycles
y ((median TTR in Phase 2))
 Surgical resection of “stable” target lesions allowed after Week 32
 2 CRs by histology in Phase 2
 Primary
y endpoint:
p response
p rate at ≥24 weeks
 All 15 responders in Phase 2 had durable responses (> 6 mo.)
 Few DTIC / TMZ durable responders (historical data)
 Allovectin-7® Phase 3 Trial
Pivotal Design Accepted by FDA under SPA
 Superiority trial vs
vs. first-line chemotherapy
 Planned 375 recurrent melanoma patients
 Chemo-naïve, no visceral metastases, normal LDH
 2:1 randomized vs. DTIC/TMZ control
 RECIST criteria optimized for immunotherapy
 Response rate at ≥24 weeks (after 3 cycles)
 90% powered to detect a ≥10% difference in primary endpoint
 90% powered to detect a survival difference of 18 vs 11 months
 AnGes MG funding full est. $23 million trial cost
 Enrollment completed February 2010 (n=390)
 Database
D t b llock
k expected
t d 2H11

11
Allovectin-7
Allovectin 7® Summary
 First-in-class systemic immunotherapy
 Unique mechanism complementary to other therapies
 Convenient outpatient administration
 Excellent safety profile (>800 patients)
 Initial application in metastatic melanoma
 Promising clinical benefit
f observed in Phase 2
(response rate, duration of response and survival)
 Enrollment completed in pivotal Phase 3 under SPA
 Orphan Drug and Fast Track designations in the U.S.
 Commercially viable product with broad potential solid
tumor applications