# Presentation: 089040

**Paul Goldfarb, M.D****.**

**Grand Rounds 2005**

## Inovio’s Proprietary Medpulser® System

- 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

**Notes:**
...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???...

## 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.

## Therapeutic Platform Based on Electroporation

**Cell Membrane**
**Before Pulse**

**Cell Membrane**
**During Pulse**

**Cell Membrane**
**After Pulse**
- (Cell returns to original state)

***A simple and effective system of delivering drugs or genes into cells***

**Electroporation**

**DC**

**Notes:**
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!!!   

## Cancer Therapy Procedure Utilizing EPT

***Very effective treatment requiring low level of technical skills***

- DC

- Electroporation

- Cell Poration,
- drug enters cells

- Injection of
- Bleomycin

- Pulsing the
- Tumor withapplicator

- Cells Reseal
- And Die

- Drug Surrounds
- Tumor Cells

**Electroporation Therapy (EPT)**

## EPT Pre-clinical & Clinical Experience

***human***

***in vitro***

***in vivo***

- 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

***Tumor Type***

***EPT is efficacious across tumor types***

## Electroporation Therapy in Head and Neck Cancer

- Patient 002: lateral tongue cancer

- The tumor is injected with Bleomycin.

## Electroporation Therapy in Head and Neck Cancer

**Patient 002: EPT**

- Electroporation Therapy (EPT) is applied with the applicator.

## Electroporation Therapy in Head and Neck Cancer

**Patient 002: 4 weeks post EPT**

- The tumor has a definitive margin after 4 weeks.

## Head & Neck Cancer Clinical Data

**Patients had a complete response rate of 80%**

**Phase II, Recurrent Late Stage H&N Tumors: N.A. and Europe**

**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

**Total**

**	****69****	****54****	****26%****	****32%****	****57%**

-  **Bleo Only**

**	****Tumors****	****Patients****	****CR%****	**** PR%**** **
**	****37****	****25****	****0****	****3**

**N. America I****N. America II**
**Europe**

**	****Tumors****	****Patients****	****CR%****	**** PR% ****	****OR%**
**	****20****	****17****	****30****	****25****	****55**
**	****31****	****25****	****19****	****39****	****58**
**	****18****	****12****	****28****	****28****	****56**

**Bleo & EPT**

**	****Tumors****	****Patients****	****NED****	**** ED**** **
**	****20****	****20****	****16****	****4**

** ****Europe**

***Excellent response rate in newly diagnosed H&N cancer patients***

## EPT Compared to Surgery

- 	•	Equivalent disease control
- 	•	Better tissue preservation
- 	•	Better function preservation
- 	•	Less cost

## 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.

## 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

## 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

## 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

## 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.

## 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.