1. Grand Rounds 2005
Paul Goldfarb, M.D.

2. Inovio’s Proprietary Medpulser® System
Generator:
• Capable of several thousand treatments
• Generates square wave DC current
Applicator:
• One per patient/treatment
• Usage restricted by smart-chip
• Sizeable gross margin
...this what out treatment system looks like...generator-applicator
...revenue based on the classic razor,razor blade model, we will make money by selling single use ,disposable applicators that do not allow re- steriliaztion...
...very hi gross margin business...
...how does this applicator distroy solid tumors???...

3. Family of Applicators Adjustable angle applicators
allow the angle of the needle probe to applicator handle
to be infinitely adjusted from 0º to 90º, permitting the physician to treat tumors on the lateral aspect of organs.
Adjustable length applicators utilize their needle shield to adjust needle length by twist clicking into stops set from 0 to 3cm in 0.5cm increments.

4. Therapeutic Platform Based on ElectroporationDC
underlying technology is electroporation. it is the use of electric fields to induce TRANSIENT pores into the cell memberane without DAMAGING it... here we see..
...these pores have a dramatic impact on enteryt of maolecules into cell, FOR EG. bleo uptake increases by several thousand time by inducing a electric field for a few seconds or it increas the uptake of plasmid DNA by over a hundred times with less then one second pulse!!!
Cell Membrane
Before Pulse
Cell Membrane
During Pulse
Cell Membrane
After Pulse
(Cell returns to original state)
Electroporation applies brief electrical pulses, inducing pores to open in the cell membrane and dramatically increasing uptake of useful drugs, genes & DNA vaccines
A simple and effective system of delivering drugs or genes into cells

5. Cancer Therapy Procedure Utilizing EPT
Injection of
Bleomycin
Electroporation Therapy (EPT) DC
Pulsing the
Tumor with applicator
Electroporation
Drug Surrounds
Tumor Cells
Cell Poration,
drug enters cells
Cells Reseal
And Die
Very effective treatment requiring low level of technical skills

6. EPT Pre-clinical & Clinical Experience
Tumor Type
in vitro
in vivo
human
ovarian
endometrial
prostate
hepaticellular carcinoma
Lewis lung carcinoma
non-small cell lung
fibrosarcoma
glioma
basal cell carcinoma
melanoma
Kaposi’s sarcoma
adenocarcinoma
squamous cell carcinoma
oral, head and neck
pancreatic
liver
EPT is efficacious across tumor types

7. Electroporation Therapy in Head and Neck Cancer
Patient 002: lateral tongue cancer
The tumor is injected with Bleomycin.

8. Electroporation Therapy in Head and Neck Cancer
Patient 002: EPT
Electroporation Therapy (EPT) is applied with the applicator.

9. Electroporation Therapy in Head and Neck Cancer
Patient 002: 4 weeks post EPT
The tumor has a definitive margin after 4 weeks.

10. Head & Neck Cancer Clinical Data
Phase II, Recurrent Late Stage H&N Tumors: N.A. and Europe
Bleo Only
Bleo & EPT
Tumors Patients CR% PR%
Tumors Patients CR% PR% OR%
N. America I N. America II
Europe
Total
% 32% 57%
Market Seeding, Newly Diagnosed H&N Tumors: Europe
CR = Complete Response : Tumor shrinkage of 100%
PR = Partial Response : Tumor shrinkage of 50% or greater
OR = Objective Response : Clinical Response +
Partial Response
NED = No Evidence of Disease at treatment site on histological examination 4 weeks post treatment
ED = Evidence of Disease
Tumors Patients NED ED
Europe
Patients had a complete response rate of 80%
Excellent response rate in newly diagnosed H&N cancer patients

11. EPT Compared to Surgery
• Equivalent disease control
• Better tissue preservation
• Better function preservation
• Less cost

12. Inovio Biomedical Corporation
Our Perception:
A NOVEL ABLATION SYSTEM THAT USES A WELL CHARACTERIZED DRUG IN A PREVIOUSLY APPROVED ROUTE OF ADMINISTRATION TO ABLATE MALIGNANT TISSUE AND SPARE NON-MALIGNANT TISSUES IN CONJUNCTION WITH A DEVICE THAT ADMINISTERS BRIEF LOCALIZED ELECTRIC PULSES.
Our Regulatory Pathway as defined by our RFD:
A COMBINATION PRODUCT WITH PRIMARY REVIEW BY CDER AND CONSULTATIVE REVIEW BY CDRH WITH A RECOMMENDATION TO CONSIDER 510-K SUBMISSION FOR THE DEVICE AT TIME OF REVIEW.

13. Inovio Biomedical Corporation
Original Phase III study design:
A standard survival based study in patients with end stage disease where all received systemic therapy and the study group received EPT. The primary endpoint was survival
Issues:
• A local therapy has no benefit if the total tumor burden is not addressed by the intervention.
• There is no clinical benefit [survival] to local therapy use in patients with end stage disease and this therapy would not be offered to patients in this clinical setting

14. Inovio Biomedical Corporation
Current Phase III study design:
• A study comparing the efficacy of EPT to surgery in patients with localized recurrent disease or second primary disease
• The endpoint is enhanced preservation of function and appearance. Survival and local control will be no worse with EPT

15. Inovio Biomedical Corporation
Bleomycin issues:
• A well characterized generic drug
• A Class 1 generic drug for parenteral administration
• The device acts with a class of drugs and not a “specific drug”
• Genetronics is not the MA holder for Bleomycin & will not bring the drug into commerce
• No interest on the part of current license holders to relabel the drug

16. Inovio Biomedical Corporation
Resolution developed with the FDA:
• The label, included with each disposable applicator, will incorporate all relevant information regarding the use of the drug Bleomycin when used as part of an EPT procedure
• Genetronics will monitor the available formulations of bleomycin on a routine basis to ensure continued constancy of formulation. This is already assured by the drug classification
• The final approval will be through a PMA granted by CDRH with a collaborative review by CDER.

17. Inovio Biomedical Corporation
Implications:
• New indications may not require relabeling of the drug and will be reflected in changes to the device label.
• Once initial safety issues related to Bleomycin have been reviewed by CDER, future efficacy assessments of this ablation technology might be reviewed by CDRH and approved as supplements to a PMA.
• THIS MODEL PROVIDES A INOVATIVE, FLEXIBLE, PATHWAY TO REVIEW AND APPROVE DRUG- DEVICE COMBINATION PRODUCTS THAT USE CERTAIN GENERIC DRUGS.